Century Therapeutics, Inc. · NASDAQ:IPSC
Century Therapeutics — Technical Presentation (December 2021)
62 slides from Century Therapeutics's technical presentation, Dec 16, 2021
Slide 1: Virtual R&D Update
VIRTUAL R&D UPDATE December 16, 2021
Slide 2: Forward-Looking Statements
2 2 FORWARD-LOOKING STATEMENTS This presentation contains forward-looking statements within the meaning of, and made pursuant to the safe harbour provisions of, The Private Securities Litigation Reform Act of 1995. All statements contained in this document, other than statements of historical facts
Slide 3: Agenda
3 3 AGENDA iPSC Cell Therapy Platform and Strategy Lalo Flores, PhD, CEO CNTY-101 Update Hy Levitsky, MD, President of R&D Treatment Paradigms and Unmet Need in B-Cell Malignancies Eduardo Sotomayor, MD, Director of Cancer Institute at Tampa General Hospital ELiPSE-1: CNTY-101 Phase 1 Trial Nick Tre
Slide 4: iPSC Cell Therapy Platform and Strategy
IPSC CELL THERAPY PLATFORM AND STRATEGY Lalo Flores ǀ CEO
Slide 5: Century's Next Generation iPSC Technology Platform
5 5 CENTURY’S NEXT GENERATION iPSC TECHNOLOGY PLATFORM Fully integrated discovery and development engine in place Precision gene editing Advanced manufacturing Allo-Evasion™ Protein engineering iPSC-derived NK cells iPSC-derived T cells Comprehensive allogeneic iPSC- based cell platform
Slide 6: Century's Differentiated Strategy
6 6 CENTURY’S DIFFERENTIATED STRATEGY CNTY-101 HLA-I Knockout IL-15 Safety switch HLA-II Knockout CD19 CAR Allo-evasionTM edits HLA-E • CD19 targeted iNK product with best-in-class potential • First cell product candidate with 6 gene edits introduced with CRISPR-HDR • Incorporates Allo-evasion gene
Slide 7: Century's iPSC-Derived CAR-T Platform (CAR-iT)
7 7 CENTURY’S IPSC-DERIVED CAR-T PLATFORM (CAR-IT) • Preclinical data supports decision to prioritize γδ iT platform for first CAR-iT products • γδ iT cells have potential for enhanced expansion and trafficking to non-hematopoietic compartments • Preferred choice for solid tumor pipeline • CNTY-102
Slide 8: Pipeline
8 8 Product iPSC Platform Targets Indications Ownership Expected IND Submission Discovery Preclinical Phase 1 Phase 2 Phase 3 CNTY- 101 iNK CD19 B-Cell Malignancies Mid 2022 CNTY- 103 iNK CD133 + EGFR Glioblastoma 2023 CNTY- 102 iT CD19 + CD79b B-Cell Malignancies 2024 CNTY- 104 iNK Multi- specific
Slide 9: Anticipated 2022 R&D Catalysts
9 9 ANTICIPATED 2022 R&D CATALYSTS • CNTY-101: IND filing and Phase 1 start • CNTY-103: Initiation of IND enabling activities • Future pipeline candidates • Disclosing multiple updates at medical and scientific congresses throughout 2022 Pipeline Platform
Slide 10: CNTY-101 Update
CNTY-101 UPDATE Hy Levitsky, MD ǀ President of R&D
Slide 11: Distinct Biology of NK Cells vs T Cells
11 11 Distinct Biology of NK cells vs T cells Influence on Platform Development NK vs T CELL BIOLOGY Proliferative capacity T cell >> NK cell Persistence/memory T cell >> NK cell Pharmacokinetics Cmax and AUC after single dose: T cells > NK cells Trafficking NK cell: lympho-hematopoietic compartment
Slide 12: NK Cell-Based Therapies Show Promising Early Signals in R/R NHL
12 12 NK CELL-BASED THERAPIES SHOW PROMISING EARLY SIGNALS OF SAFETY AND EFFICACY IN R/R NHL iC9/CAR.19/IL15 -Transduced CB-NK GDA-201 FT516 FT596 Regimen - + IL-2 + rituximab + anti-CD20 mAb + IL-2 Monotherapy + anti-CD20 mAb CR, % 67% 65% 44%* 30%* 56%* CRS, all G (G≥3) No CRS No CRS No CRS 8% G1
Slide 13: Potential Advantages of Redosing
13 13 POTENTIAL ADVANTAGES OF REDOSING • Experience with autologous CAR-T established the impact of “drug exposure” (PK AUC) on disease response • Repeat dosing of CAR-iNK cells can extend drug exposure to achieve potentially deeper and more durable remissions • Infusion of fresh cells may mitigate
Slide 14: Allo-Evasion 1.0 Designed to Overcome Host vs Graft Rejection
14 14 ALLO-EVASIONTM 1.0 DESIGNED TO OVERCOME 3 MAJOR PATHWAYS OF HOST VS GRAFT REJECTION β2M KO (HLA-I) HLA-E KI CIITA KO (HLA-II) CD8+ T Cell CD4+ T Cell NK cell Deletion of β 2M, a protein required to express HLA-1 on the cell surface prevents recognition by CD8 T cells Knock out of CIITA elimina
Slide 15: Allo-Evasion 1.0 Edits Render Cells Resistant to T and NK Killing
15 15 ALLO-EVASIONTM 1.0 EDITS RENDER CELLS RESISTANT TO T CELL AND NK CELL KILLING Pan-HLA Class I Primary blood NK Unedited iNK β2M KO (Edited) iNK Isotype control stain Donor 1 Donor 2 0 10 20 30 40 50 % Specific Cell Death β2M KO iNK HLA-E+ iNK *p<0.02 ***p<0.0001 N=5 healthy donors * *** 0 500
Slide 16: Illustrative Potential of Allo-Evasion on Pharmacokinetics and Repeat Dosing
16 16 ILLUSTRATIVE POTENTIAL OF ALLO-EVASIONTM ON CELLULAR PHARMACOKINETICS AND REPEAT DOSING Repeat doses With Allo-EvasionTM engineering Without Allo-EvasionTM engineering Time Cell count Initial dose Minimum threshold to maintain pharmacological pressure
Slide 17: IL15 and IL2 Improve CAR-iNK Persistence and Tumor Clearance
17 17 INTRINSIC IL15 AND EXTRINSIC IL2 IMPROVE CAR-iNK PERSISTENCE AND TUMOR CLEARANCE IN TISSUES (LUNG) CAR-iNK CAR/IL15-iNK CAR-iNK CAR/IL15-iNK 0.0 0.5 1.0 1.5 2.0 2.5 iNK cells (% of live cells) Blood Lung 20 days CD19CAR+IL15+iNK day 1 +/- rhIL2 days 1,3,5 Sampling day 7 +/- Transgenic IL15 Tra
Slide 18: CNTY-101 Demonstrates Robust Tumor Killing In Vitro and In Vivo
18 18 CNTY-101 DEMONSTRATES ROBUST TUMOR KILLING IN VITRO AND IN VIVO HLA-I Knockout IL-15 Safety switch HLA-II Knockout CD19 CAR CNTY 101 HLA-E 0 100 200 0 5×106 1×107 NALM-6 Lymphoma Time Elapsed (hours) RCU x µ m 2 /Well CNTY-101 + NALM-6 NALM-6 Alone 0 5 10 15 20 25 0 2.0×10 8 4.0×10 8 6.0×10 8
Slide 19: Summary
19 19 SUMMARY • CNTY 101 is Century’s first iPSC-derived NK cell therapy candidate for the treatment of CD19+ B cell malignancies • Incorporates a comprehensive gene editing strategy to evade CD4+ and CD8+ T cell and NK cell mediated allo-rejection and have potentially favorable pharmacokinetics • P
Slide 20: Treatment Landscape of Non-Hodgkin's Lymphomas
Eduardo M. Sotomayor, MD Director, TGH Cancer Institute Professor, Morsani College of Medicine University of South Florida Treatment Landscape of Non- Hodgkin’s Lymphomas: It seems to be a crowded field…but it depends how you see it and/or approach it…..
Slide 21: Timeline of Newer Agents for B-cell NHL
Timeline of Newer Agents for B-cell NHL Ofatumumab • First approved for CLL in 2009 • Extended treatment for recurrent or progressive CLL • + Fludarabine and Cyclophosphamide for Relapsed CLL Lenalidomide • Relapsed MCL after ≥2 prior therapies Ibrutinib • MCL ≥ 1 prior therapies • CLL/SLL, del(17p)
Slide 22: Targeted Therapy and Immunotherapy of B-cell NHL
Targeted Therapy and Immunotherapy of B-cell NHL Rituximab Ofatumumab Obinutuzumab Polatuzumab vedotin Loncastuximab tesirine Tafasitamab (MOR208) Ublituximab Copanlisib Duvelisib Idelalisib Umbralisib Venetoclax Ibrutinib Acalabrutinib Zanubrutinib Pirtobrutinib (Loxo 305) Axi-cel / Liso-cel Tisage
Slide 23: Immunotherapy: Targeting CD19 and CD20
• CD19 is an enticing target for novel approaches: • Tafasitamab, anti-CD19 antibody (+/- Lenalidomide) • Loncastuximab Tesirine (Anti-CD19 Antibody-Drug Conjugate) • CD20 is….again an enticing target for bi-specific antibodies: • Several bi-specific directed T-cell engager (BITE) targeting CD20 and
Slide 24: Checkpoint Blockade in B-cell NHL
• Unlike the success in Hodgkin’s lymphoma, clinical trials with checkpoint blockade antibodies in relapsed/refractory B-cell NHL have been disappointing so far: • Despite malignant B-cells being surrounded by an “army” of T-cells • Role of the immunosuppressive Tumor Microenvironment (TME). TME is
Slide 25: Bispecific Antibodies
Glofitamab ASH 2021.….the saga continues: Bispecific Antibodies
Slide 26: Game Changer: Bispecific Antibodies
“Game changer”: Bispecific antibodies Human anti-CD20 x anti-CD3 Monoclonal Bispecific Antibody Cross-linking results in targeted activation of local T-cells and T-cell-mediated killing of CD20+ B-cells (independently of TCR-mediated recognition) Cell lysis T-cell CD20+ target cell CH3 CH2 CH3 CH2 *
Slide 27: Bi-Specific Antibodies: Safety
Bi-Specific Antibodies: Safety Antibody CD20/CD3 Glofitamab Mosunetuzumab Odronextamab Epcoritamab N 64 ( > 600 ug) 131 136 58 CRS any CRS >3 63.5% 3.8% 28.9% 1.1% 61% 7.3% 59% 0 NT any NT >3 43.3% NR 49% 1.1% NR 3.6%% 6.9% 3.4% CRS, cytokine release syndrome; NT, neurotoxicity
Slide 28: Immunotherapy: Targeting CD19 in B-cell Lymphoma
• Autologous CD19 CAR T-cells have shown significant efficacy in patients with relapsed/refractory CD19 positive DLBCL and other B-cell lymphomas. • Three platforms are FDA-approved (Axi-cel, Tisa-cel and Liso-cel) for DLBCL • One platform approved for MCL (Brexucabtagene autoleucel) • One platform
Slide 29: Will CD19 CAR T-cell Replace Autologous Transplant for DLBCL?
ASH 2021: Will CD19 CAR T-cell Replace Autologous transplant for DLBCL? ZUMA-7 ASH 2021: Axi-cel BELINDA Tisagenlecleucel High-risk DLBCL: .. Refractory to first-line tx .. Relapsed after first-line tx CAR T-cell therapy Salvage therapy/ auto-transplant NCT03391466. NCT03570892. NCT03575351. Positiv
Slide 30: Bispecific Antibodies vs. Autologous CAR T-Cells
Bispecific Antibodies vs. Autologous CAR T-Cells T Tumor cell Characteristic Bispecific Antibodies CAR T-Cell Therapy Preparation “Off the shelf” In vitro manufacturing (3-4 wks) Dosing Repetitive Single (following lymphodepleting CT) CRS incidence Less Greater T Bispecific antibody Cytotoxic T lymp
Slide 31: Targeted Therapy: Many Successes but Also Limitations
• Novel targeted agents either alone or in combination are improving clinical outcomes of patients with B-cell lymphomas, mainly in the relapsed/refractory setting • Some of them have been (or are being) evaluated as frontline therapy alone or in combination in some B-cell malignancies (CLL/SLL; MCL
Slide 32: Unmet Needs + Good Science = Opportunities
Unmet needs + Good Science = Opportunities in a “crowded” Therapeutic Landscape I. Good Science: - Beyond T-cell immunotherapies… Harnessing Innate Immunity - Genetically engineered NK cells - Genetically engineered Macrophages II. Unmet Needs in Non-Hodgkin’s lymphomas - Difficult to treat lymphoma
Slide 33: Emerging Needs in Non-Hodgkin's Lymphomas
II. Emerging Needs in Non-Hodgkin’s lymphomas - Innate or acquired resistance to novel agents - BTK resistance (MCL, CLL, WM, MZL) - CD19 CAR T-cells (DLBCL, MCL, FL)…. CLL - Double refractory (FL, MCL) Unmet needs + Good Science = Opportunities in a “crowded” Therapeutic Landscape III. “Wide open”
Slide 34: Off the Shelf Engineered Cellular Products: Allogeneic Therapies
ASH 2021:“Off the Shelf” Engineered Cellular Products: Allogeneic Therapies Advantages • Eliminates the manufacturing time and allows true point of care administration • Expand access to therapy (ie, leukopenic patients) • Improve safety through genetic manipulation • Can scale to much larger number
Slide 35: Sources of Allogeneic Cells
ASH 2021: Sources of Allogeneic Cells Pluripotent stem cells • iPSC (inducible pluripotent stem cells) • T-iPSC (T) - Self-renewing. Expanded indefinitely Homogenous product available in large batches -Complex editing is possible -Complex differentiation process is a challenge Modified from Crooks,
Slide 36: Conclusions
Conclusions • Despite the progress that has been made in the treatment of NHL, there are still several unmet needs • Emerging needs as a result of changing treatment landscape • ie resistance to targeted/immune based therapies • Strategies to harness innate immunity represent a compelling opportunit
Slide 37: Thank You
esotomayor@tgh.org THANK YOU !
Slide 38: CNTY-101 Phase I Trial Design
CNTY-101 PHASE I TRIAL DESIGN Nick Trede, MD, PhD ǀ VP Early Clinical Development
Slide 39: CNTY-101: Allogeneic iPSC-Derived CAR-iNK Targeting CD19
39 39 CNTY-101: AN ALLOGENEIC, iPSC-DERIVED CAR-iNK PRODUCT CANDIDATE TARGETING CD19 FOR R/R B-CELL MALIGNANCIES CNTY-101 has the potential to change the lymphoma patient treatment paradigm • Potentially treat patients immediately upon diagnosis • Based on Allo-evasion and anticipated ability to giv
Slide 40: ELiPSE-1 Study: Key Selection Criteria
40 40 THE ELIPSE-1 STUDY: A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF CNTY-101 IN SUBJECTS WITH RELAPSED OR REFRACTORY CD19 POSITIVE B CELL MALIGNANCIES - KEY SELECTION CRITERIA INCLUSION CRITERIA • Aggressive NHL: DLBCL, HGBL, PMBCL MCL, tFL, FL3B • Indolent NHL: FL, MZL • At least 2 prior lines of
Slide 41: ELiPSE-1 Objectives
41 41 ELiPSE-1 OBJECTIVES Primary Maximum-tolerated dose (MTD) or maximum administered dose regimen of CNTY-101 (dose and schedule of CNTY-101 with IL-2) Recommended phase 2 regimen (RP2R) of CNTY-101 + IL-2 Secondary Antitumor activity PK profile Safety and tolerability at RP2R Time to dosing Explo
Slide 42: Timeline (Single Dose) and Assessments
42 42 TIMELINE (SINGLE DOSE) AND ASSESSMENTS LTFU Study Lymphode pletion Efficacy assessment D28 D1 CNTY-101 infusion IL2 infusion daily Screening, enrollment Safety evaluation period Frequent visits & safety assessments M4 M7 M10 M13 M19 M24 SAFETY: CONTINUOUS ASSESSMENT • Dose-limiting toxicities
Slide 43: CNTY-101 Exploratory Studies Within ELiPSE-1
43 CNTY-101 EXPLORATORY STUDIES WITHIN ELIPSE-1 r 1 5 , 2 0 2 1 3 CRP IL - 15 % VAF Lymphodepletion, Century product infusion CNTY-101 Blood Serum/ Plasma Tumor Biopsy Mechanism of Action/ Resistance Safety & Other Efficacy Correlates Pharmacokinetics: Expansion & Persistence Phenotype & function Ho
Slide 44: ELiPSE-1 Treatment Schema (1)
44 44 ELiPSE-1 TREATMENT SCHEMA (1) EVALUATION OF SINGLE DOSE ESCALATION AND IL-2 Part 1 With IL-2 30e6 x1 Schedule A 100e6 x1 1000 e6 x1 300e6 x1 100e6 x1 Dose Level (DL) Fallback Dose Starting Dose DL-1 DL1 DL2 DL3 No IL-2 Safety Review Committee reviews data and implements dosing decisions First
Slide 45: ELiPSE-1 Treatment Schema (2)
45 45 ELiPSE-1 TREATMENT SCHEMA (2) EVALUATION OF ADDITIONAL CYCLE(S) Safety Review Committee reviews data and implements dosing decisions Part 1 With IL-2 30e6 x1 Schedule A 100e6 x1 1000 e6 x1 300e6 x1 Redosing for patients who demonstrate clinical benefit post-FDA approval Dose Level (DL) Fallbac
Slide 46: ELiPSE-1 Treatment Schema (3)
46 46 ELiPSE-1 TREATMENT SCHEMA (3) EVALUATION OF MULTIPLE DOSING SCHEDULE Schedule B opens once MTD or max dose in Schedule A is determined. Starting Schedule B Dose: 1/3 current dose, given 3 times, 1 week apart Part 1 With IL-2 Part 2 Dose Level (DL) 30e6 x1 Schedule A 100e6 x1 1000 e6 x1 300e6 x
Slide 47: ELiPSE-1 Treatment Schema (4) Key Milestones
47 47 ELiPSE-1 TREATMENT SCHEMA (4) KEY MILESTONES Schedule B opens once MTD or max dose in Schedule A is determined. Starting Schedule B Dose: 1/3 current dose, given 3 times, 1 week apart Part 1 With IL-2 Part 2 Dose Level (DL) 30e6 x1 Schedule A 100e6 x1 1000 e6 x1 300e6 x1 RP2R To N=20 subjects*
Slide 48: Summary
48 48 SUMMARY • Century's iPSC-derived NK cell therapies - CNTY-101 • Precise, multiple genome edits • Unlimited supply • Homogeneous product • Off-the-shelf • Allo-evasion • Potential for excellent safety profile and outpatient treatment • Potential for promising efficacy, access to redosing and re
Slide 49: Century iT Platform Update
CENTURY IT PLATFORM UPDATE Luis Borges, PhD ǀ CSO
Slide 50: We Engineer iPSCs to Generate iT and iNK Cell Cancer Therapies
50 50 AT CENTURY, WE ENGINEER iPSCs TO GENERATE iT AND iNK CELL CANCER THERAPIES • CAR-TCR • Allo-evasionTM • TME modulation • Safety • Consistency • Yield • Fitness Candidate Generation Manufacturing iPSC Engineered iPSC MCB Gene editing & cell engineering Process optimization & scale up iNK cell i
Slide 51: Century's iT Cell Platform: TrueT Cells Expressing Trusted TCRs
51 51 CENTURY’S iT CELL PLATFORM THE CONCEPT OF TrueT CELLS EXPRESSING TRUSTED TCRs T cells express two major types of TCRs • αβ TCRs: recognize hypervariable peptide antigens in the context of MHC molecules; responsible for GvHD • γδ TCRs; recognize invariant antigens such as phospho- antigens inde
Slide 52: γδ T Cells Offer Unique Advantages for Cancer Therapy
52 52 γδ T CELLS SHARED PROPERTIES OF ADAPTIVE AND INNATE IMMUNE CELLS AND OFFER UNIQUE ADVANTAGES FOR CANCER THERAPY Property αβ T cells γδ T cells Low risk of GvHD - Innate anti-tumor killing - TCR-mediated tumor killing MHC-independence for TCR- mediated killing - Recognition of molecular pattern
Slide 53: Multiple TiPSC Lines Generated from γδ T Cells
53 53 CENTURY HAS GENERATED MULTIPLE TiPSC LINES THROUGH THE REPROGRAMING OF γδ T CELLS CD3+ TCRgd+ Vg9+ Vd1+ Vd2+ 0 25 50 75 100 Percent Day 0 Day 7 Day 9 Day 12 Day 14 Expansion Of γδ T Cells From Blood TiPSC Colonies Derived From γδ T Cells
Slide 54: Reproducible Protocols to Differentiate γδ TiPSC Lines
54 54 CENTURY HAS DEVELOPED HIGHLY REPRODUCIBLE PROTOCOLS TO DIFFERENTIATE γδ TiPSC LINES CD34 CD43 CD45 CAR Side scatter 0 50 100 Day % of cells expressing 0 7 14 21 28 CD34 CD45 CD3/TCRγδ CD7 98% CAR+ cells ~100% TCR+ γδ iT cells
Slide 55: γδ CAR-iT Cells Kill Tumors as Efficiently as CAR-T Cells
55 55 γδ CAR-iT CELLS KILL TUMORS AS EFFICIENTLY OR BETTER THAN CAR-T CELLS 0 20 40 60 80 0 20 40 60 80 100 Time (hours) Normalized Target count (% of cell line alone control) 0 20 40 60 80 0 20 40 60 80 100 Time (hours) Normalized Target count (% of cell line alone control) NALM-6 Lymphoma (CD19Hi)
Slide 56: γδ CAR-iT Cells Kill Lymphoma Through Multiple Rounds Without Exhaustion
56 56 γδ CAR-iT CELLS KILL LYMPHOMA CELLS THROUGH MULTIPLE ROUNDS OF KILLING WITHOUT REACHING EXHAUSTION 0 100 200 300 0 500000 1000000 1500000 2000000 2500000 Time Elapsed (hours) Red object total area ( μ m 2 /image) 0 100 200 300 0 500000 1000000 1500000 2000000 2500000 Time Elapsed (hours) Red o
Slide 57: γδ CAR-iT Cells Do Not Release Inflammatory Cytokines
57 57 γδ CAR-iT CELLS DO NOT RELEASE INFLAMMATORY CYTOKINES WHEN KILLING TARGETS γδCAR-iT CAR-T A CAR-T B CAR-T C IFN-γ T cells from 3 healthy donors 5:1 1:1 1:5 Target Alone 0 500 1000 1500 2000 Killing Asasy E:T Ratio IFN- γ (pg/ml) 5:1 1:1 1:5 Target Alone 0 50 100 150 Killing Asasy E:T Ratio TNF
Slide 58: CAR-γδ iT Cells Have Robust Anti-Lymphoma Activity In Vivo
58 58 CENTURY’S CAR-γδ iT CELLS HAVE ROBUST ANTI-LYMPHOMA ACTIVITY IN VIVO 0 2×108 4×108 6×108 8×108 1×109 1.2×109 Day Post-tumor Implantation Average Radiance (p/s/cm²/sr) ± SEM 21 0 7 14 Tumor Burden 1 dose on day 1 3 doses on days 1, 8, and 15 Control tumor only NALM-6 Lymphoma Xenograft
Slide 59: Next Steps
59 59 NEXT STEPS • Complete the reprograming of clinical grade γδ TiPSC lines from multiple donors • Engineer core features on novel γδ T-IPSC lines to generate a common TiPSC progenitor for multiple iT cell product candidates • Generate new iT product candidates for solid tumors and heme malignanci
Slide 60: Century's iPSC-Derived γδ T Cells in Action
60 60 CENTURY’S iPSC-DERIVED γδ T CELLS IN ACTION
Slide 61: Thank You
THANK YOU
Slide 62: OsENTURY
OsENTURY
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