Legend Biotech Corp. · NASDAQ:LEGN
Legend Biotech — Investor Day (October 2021)
92 slides from Legend Biotech's investor day presentation, Oct 18, 2021
Slide 1: R&D Day
Legend Biotech R&D Day October 18, 2021
Slide 2: Forward-looking Statements
Forward-looking Statements Statements in this report about future expectations, plans and additional safety and/or efficacy data or analysis of data, or prospects, as well as any other statements regarding matters that are government regulation generally; unexpected delays as a result of not histori
Slide 3: Agenda
Agenda Welcome Jessie Yeung, Head of Corporate Finance 10:00 a.m. – 10:05 a.m. Introduction Dr. Ying Huang, CEO & CFO 10:05 a.m. – 10:15 a.m. Global BCMA Program Dr. Lida Pacaud, VP of Clinical Development 10:15 a.m. – 11:00 a.m. Steve Gavel, VP of Commercial Development Coffee Break 11:00 a.m. – 11
Slide 4: Introduction
Introduction Ying Huang, Ph.D. Chief Executive Officer & Chief Financial Officer
Slide 5: Key Milestones
Key Milestones Corporate and regulatory 1st US IND Nasdaq IPO PDUFA Phase 1b/2 IND Legend Biotech goes public, The cleared by US FDA raising $487 million, Prescription including the greenshoe Drug User Fee option Act target action date is November 29, 2021 for cilta- Legend Founded 1st MM Patient ce
Slide 6: Our Presenters
Our Presenters Lida Pacaud, M.D. Steve Gavel Frank Fan, M.D., Ph.D. Vice-President, Clinical Development Vice-President, Commercial Development Chief Scientific Officer, Co-Founder A trained physician, Dr. Lida Pacaud formerly Steve Gavel has spent 20 years conducting Dr. Frank Fan is an applied led
Slide 7: Pioneering Cellular Therapy
Pioneering Cellular Therapy Multiple armored CAR-T In-house antibody generation strategies to overcome and CAR-T-specific functional challenges in treatment of solid screening technologies Antibody Armoring tumors screening & strategy for engineering solid tumors Diverse allogeneic platforms, includ
Slide 8: What inspires us?
What inspires us? LEGEND-2 Patient #6 Total dose 0.5 x106 CAR+ cells/kg Day 1 Day 19 Mar 2019 Oct 2020 As of May 2021*: • D20: λ light chain decreased from 1770 to 0.48 mg/L Disease-free • Assessed as MRD- CR without additional maintenance treatment 1210 1312 1414 1590 June 2016 Sept 2019 Oct 2020 C
Slide 9: 5-year follow-up
5-year follow-up BIOTECH
Slide 10: Advancing Treatment Options for Multiple Myeloma
Advancing Treatment Options for Multiple Myeloma Lida Pacaud, M.D. Vice President of Clinical Development Steve Gavel Vice President of Commercial Development 10
Slide 11: Current Clinical Development Plan
Current Clinical Development Plan Ciltacabtagene autoleucel (cilta-cel) CARTITUDE-1 CARTITUDE-4 Phase 1b/2, registrational Phase III, 1-3 prior (ASCO 2021 update) lines MM CARTITUDE-2 CARTITUDE-5 Phase II, Multi-cohort Phase III, Newly study in various MM diagnosed, transplant settings not intended/
Slide 12: CARTITUDE-1: Unprecedented responses in relapsed/refractory multiple myeloma
CARTITUDE-1: Unprecedented responses in relapsed/refractory multiple myeloma (ASCO 2021) N=97 • 18 months median follow up ORR: 97.9% • 97.9% ORR 100 - 94.8% ≥VGPR - 80.4% sCR - 91.8% MRD 10-5 negative CR (61 evaluable patients)b 80 • Response rates were comparable across different subgroups 60 80.4
Slide 13: CARTITUDE-1: Long-term clinical benefit measured by PFS
CARTITUDE-1: Long-term clinical benefit measured by PFS (ASCO 2021) • Median duration of follow-up of 18 months All Patients sCR 100 • Lower CI indicates minimum 22.8mo PFS 90 benefit in all patents 80 Survival, Patients (%) • Median PFS will mature with further follow-up Progression-Free 70 Median:
Slide 14: CARTITUDE-1 Commercial Assumptions & Implications
CARTITUDE-1 RRMM: PI, IMiD and anti-CD38 exposed Commercial Assumptions & Implications • Indication assumption* (Patients meeting label requirements) - US: 5L+ Prior lines of therapy patient opportunity ▪ US: ~12,000 - EU/JP: 4L+ Prior lines of therapy patient opportunity ▪ EU: ~6,000 Call out title
Slide 15: CARTITUDE-2: Phase II Multi-Cohort Study
CARTITUDE-2: Phase II Multi-Cohort Study in Various Multiple Myeloma Settings (n ≈ 160) Cohort A Progressive disease after 1-3 lines of MM therapy and len refractory Cohort B Early relapse: ≤12 months after frontline therapy or ≤12 months after ASCT Cohort C Induction if Bridging Lympho- Cilta-cel i
Slide 16: CARTITUDE-2 Cohort A: 95% ORR
CARTITUDE-2 Cohort A (n=20): 95% ORR in 1 – 3 prior lines RRMM (ASCO & EHA 2021) • MM after 1–3 prior lines of therapy, refractory to lenalidomide ORR: 95% • Median prior lines of therapy was 2 (range, 1-3); 1 patient 100 (19/20a) treated in an outpatient setting 90 • Median follow-up of 5.8 months
Slide 17: CARTITUDE-4: Phase III Study in 1-3 prior line RRMM
CARTITUDE-4: Phase III Study in 1-3 prior line RRMM (NCT04181827) PRIMARY OBJECTIVE • To compare efficacy (PFS) of cilta-cel infusion to the standard treatments of PVd or DPd KEY INCLUSION CRITERIA • Age ≥18 with diagnosed MM • 1–3 prior lines of therapy (PI+IMiD or PI+IMiD+CD38 exposed), and lenali
Slide 18: CARTITUDE-4 - Study Schema
CARTITUDE-4 - Study Schema 1:1 randomization PVd or DPd* Until (n=400) progress- Screening Follow-up ion Bridging Cilta-cel infusion Observation PVd or DPd* (Target: 0.75×106 CAR+ T cells/kg)** ≥1 cycle T-cell transduction and expansion to manufacture cilta-cel • Study start date: June 2020 • ~100 s
Slide 19: Myeloma RRMM Triplet Efficacy Outcomes - Current SoC
Myeloma RRMM Triplet Efficacy Outcomes - Current SoC Regimen % Len Median PFS Median PFS for Median Lines Study Name and Refractory (Months) Len Refractory of Therapy Reference Patients (Months) (Publication) DVd arm (n=251) 17.9% (DVd) 16.7 9.3 2 CASTOR; Spencer 2018 PVd arm (n=281) 71% (PVd) 11.2
Slide 20: CARTITUDE-4 Commercial Assumptions
CARTITUDE-4 RRMM: 1-3 PL (PI+IMiD exposed + lenalidomide refractory) First Phase III Global BCMA CAR-T cell therapy Clinical Trial in 1-3 prior line setting Cilta-cel indication assumption - 1-3 prior lines of therapy ▪ Does not require prior daratumumab exposure Call out title o ~80% of patients in
Slide 21: CARTITUDE-5: Phase III Study in newly diagnosed MM
CARTITUDE-5: Phase III Study in newly diagnosed MM, not intended for transplant (NCT04923893) PRIMARY OBJECTIVE • To compare efficacy of VRd followed by cilta-cel vs VRd followed by Rd therapy KEY INCLUSION CRITERIA • Newly diagnosed multiple myeloma • Not considered candidate for high-dose chemothe
Slide 22: CARTITUDE-5 - Study Schema
CARTITUDE-5 - Study Schema VRd Rd maintenance (until progression) 1:1 randomization (2 cycles) VRd induction (n=650) Screening Follow-up (6 cycles*) VRd Cilta-cel (2 cycles) Infusion Observation Bridging therapy (Target: 0.75×106 post apheresis CAR+ T cells/kg)** • Study start date: August 2021 • ~1
Slide 23: VRd Regimen in Newly Diagnosed Multiple Myeloma - Current SoC
VRd Regimen in Newly Diagnosed Multiple Myeloma - Current SoC Regimen PFS for VRd Study Name and Reference VRd arm (n=242) 43 months SWOG S0777; Durie 2017 VRd arm (n=350) 36 months IFM/DFCI2009; Attal 2017 VRd: Darzalex, Revlimid, dexamethasone 23
Slide 24: CARTITUDE-5 Commercial Assumptions
CARTITUDE-5 Frontline: Transplant not intended (TNI) First Phase 3 Global BCMA CAR-T cell therapy Clinical Trial in Frontline Setting Commercial Assumptions/Implications - Cilta-cel indication assumption Call out title ▪ 64,000 newly diagnosed patients across US/EU/Japan ▪ *Transplant not intended e
Slide 25: Clinical Program - Cilta-cel Studies in Multiple Myeloma
Clinical Program - Cilta-cel Studies in Multiple Myeloma Late Line Studies of Therapy Earlier Lines of Therapy NCT03548207 NCT04133636 • Phase 1b/2, multi-center registrational study • Global, multi-cohort study CARTITUDE-11 of cilta-cel in RRMM CARTITUDE-23 • Phase II open-label study of • Fully en
Slide 26: Conclusion: Global BCMA Program
Conclusion: Global BCMA Program • Cilta-cel has demonstrated potential best-in-class efficacy in CARTITUDE-1 study in RRMM • Preliminary data from CARTITUDE-2 shows early promise for cilta-cel in early line MM • CARTITUDE-4 is enrolling well and positions cilta-cel well in 2+ line MM Potential • CAR
Slide 27: Coffee Break
Coffee Break The presentation will resume in 10 minutes
Slide 28: In Fierce Pursuit of Novel Therapies
In Fierce Pursuit of Novel Therapies Frank Fan, M.D., Ph.D. Chief Scientific Officer 28
Slide 29: Overview Solid Tumors Allogeneic Platforms
Overview Solid Tumors Allogeneic Platforms Introduction of R&D culture Gastric cancer & Pancreatic Unique non-genome editing cancer allogeneic CAR-T platform Ab discovery expertise HCC and NSCLC Legend CAR-NK platform Diverse technology platforms SCLC 29
Slide 30: The Strengths of Our R&D Program
The Strengths of Our R&D Program CORE TECHNOLOGIES • Outstanding CAR target identification expertise • High-throughput antibody screening and engineering capability • Proprietary multi-specific CAR-T platform • A series of innovative CAR enhancing strategies • Unique non-genome editing allogeneic CA
Slide 31: Legend NGS and Bioinformatics Capabilities
Legend NGS and Bioinformatics Capabilities NGS Platform Bioinformatics Platform In-house 10X Genomics single cell sequencing platform In-house HPC and AWS cloud computation Sophisticated NGS and bioinformatician teams Target Discovery and TME Analysis Drug Product Clinical Study Validation TME cell
Slide 32: Multiple Antibody Development Platforms
Multiple Antibody Development Platforms Llama mAb development, In vivo or mouse screening pharmacology Sequencing and humanization Target screening In vitro Safety assessment pharmacology of CAR-T CAR-T sdAb Lead sdAb screening In vitro in vivo Immunization library sequence and pharmacology optimiza
Slide 33: Legend VHH-Based Multi-Specific CAR-T Platform
Legend VHH-Based Multi-Specific CAR-T Platform • Improved CAR expression and stability • Easier access to novel and hidden epitopes, which specifically facilitates the design of membrane proximal binders • Robust engineering flexibility for the design of complex multi-specific CAR 33
Slide 34: Challenges in Treating Solid Tumor by T-cell Therapy
Challenges in Treating Solid Tumor by T-cell Therapy Mackall et al., Nature Biomedical Engineering, 2018 34
Slide 35: Technologies for Conquering Solid Cancers
Technologies for Conquering Solid Cancers Conditional High affinity armor activation Reducing COGS • High specificity Armor does not alter tumor • Superior efficacy specificity over benchmarks Complementary Suite offirTechnologies CAR-driven armor Overcome TME Smart manufacture Selected binder Optim
Slide 36: Proprietary Intracellular Modulator (IM) Platform
Proprietary Intracellular Modulator (IM) Platform Modification of intracellular molecules in CAR-T cells could resist inhibitory signal from cell surface and increase their persistence and activity in tumor microenvironment. Functional mitochondria Central memory T cells 80 80 Mitotrack Red High (%)
Slide 37: Capability Summary of the Legend R&D Team
Capability Summary of the Legend R&D Team Professional IP team Highly motivated RA and PM groups Skilled professionals established a dedicated Broad suite of technologies biomarker platform CAR-T, TCR-T, allogeneic CAR-T/NK, gd- T Extensively experienced Talented analytic team on customized PD for d
Slide 38: Solid Tumors: LB1908
Solid Tumors: LB1908 Solid Tumors Allogeneic Platforms
Slide 39: LB1908: CLDN18.2 CAR-T
LB1908: CLDN18.2 CAR-T For gastric cancer and pancreatic cancer TARGET • Claudin (CLDN) are a family of tight junction proteins1 • CLDN18.2 is commonly expressed on multiple cancers including gastric cancer and pancreatic cancer 2 • CLDN18.2 is highly conservative cross species, extracellular domain
Slide 40: Claudin18.2 Expression is Gastric Tissue-restricted
Claudin18.2 Expression is Gastric Tissue-restricted Homology between CLDN18.2 and CLDN18.1 Moderate Claudin 18.1 expressed in Claudin18.2 protein expression in pit region human lung tissue (Alveolar cells) and the base of gastric glands 85% AA Identity 100% AA Identity ECL1 ECL2 T T T T M M M M 1 2
Slide 41: Claudin18.2 Protein is Widely Expressed in GC and PDAC
Claudin18.2 Protein is Widely Expressed in GC and PDAC Presence of Claudin18.2 protein in human cancer tissues Claudin 18.2 expression in gastric tumor and LN metastases (66 tissue IHC, EU) (262 cases IHC, Japan) Primaries Primaries ≥2+ in ≥60% of cells ≥2+ in ≥60% of cells Any labeling Any labeling
Slide 42: LB1908 Modality and Features
LB1908 Modality and Features • LB1908 (LCAR-C18S) consists of autologous T cells genetically modified to express a CAR utilizing a lentiviral vector • Preclinical studies demonstrate a target-specific profile of efficacy as well as safety • Highly specific VHH characterized by human frozen tissue ar
Slide 43: LB1908 VHH Binding Patterns and Performance
LB1908 VHH Binding Patterns and Performance • High specificity is the premise and cornerstone of developing a safe, live drug targeting CLDN18.2 • LB1908 VHH strongly and specifically binds to CLDN18.2, but not to CLDN18.1 43
Slide 44: LB1908 CAR-T Showed Cytotoxicity Only to Claudin18.2
LB1908 CAR-T Showed Cytotoxicity Only to Claudin18.2 • Toxicity was not shown to Claudin18.1+cells or a set of human primary cells CLDN18.1high/CLDN18.2neg CLDN18.1neg/CLDN18.2high Human Normal Primary Pulmonary Human Normal Primary Lung Human Normal Primary Pulmonary Pancreatic cancer cell line Pan
Slide 45: LB1908: Anti-tumor Efficacy in Gastric Tumor CDX Model
LB1908: Anti-tumor Efficacy in Gastric Tumor CDX Model Tumor cell s.c. Single treatment, i.v. Monitoring Model: NCG mouse (NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl) 14 days Tumor engraftment: Subcutaneous CDX xenograft (human GC cell line NUGC4, CLDN18.2+) Animal bodyweight In vivo CAR expansion Tumor
Slide 46: LB1908: Anti-tumor Efficacy in PDAC CDX Model
LB1908: Anti-tumor Efficacy in PDAC CDX Model Tumor cell s.c. 3M Single shot Treatment, tail i.v. Monitoring Model: NCG mouse (NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl) 21 days Tumor engraftment: Subcutaneous CDX xenograft (human PC cell line AsPC1.CLDN18.2) Tumor volume monitoring Animal bodyweight In
Slide 47: Human Tissue Cross-reactivity with LB1908 Antibody
Human Tissue Cross-reactivity with LB1908 Antibody Tissue IHC: 30 different normal human tissues from 3 individuals. • Tissue list • Adrenal • Ovary • Bone Marrow • Pancreas • Breast • Placenta • Cerebrum • Prostate • Cerebellum • Skin • Pituitary • Spinal Cord • Colon • Spleen • Artery • Striated m
Slide 48: LB1908 Investigator Initiated Clinical Trial
LB1908 Investigator Initiated Clinical Trial A Clinical Study to Evaluate CAR-T Cell-based Medicinal Product in the Treatment of Advanced Gastric Cancer Key Inclusion and Exclusion Criteria1 Study Endpoints Inclusion: Primary Outcome Measures: Aged 18-75 years; Claudin18.2 positive recurrent or meta
Slide 49: Study Design and Status
Study Design and Status • A Phase I, Open-Label Study Evaluating the Dose Escalation （～24 pts） Safety, Tolerability and Efficacy of LB1908, a CAR-T Cell Therapy targeting Claudin18.2 in 0.5M/kg Patients With Advanced Gastric Cancer Accelerated • Study Objectives: the safety, tolerability, PK Titrati
Slide 50: Case Report
Case Report • First dosed subject, Female/41, Gastric Adenocarcinoma, HER-2 (-), Claudin18.2 IHC (>75%,+++) - Sep 2017: radical gastrectomy - From Nov 2019 to Jul 2020: received 5 prior lines systemic treatment for recurrent disease D-5 D-4 D1 D14 D22 D30 D45 D60 D90 D180… Apheresis Pre-conditioning
Slide 51: Preliminary Sign of Clinical Response in the 1st Dosed Subject of LB1908
Preliminary Sign of Clinical Response Emerge in the 1st Dosed Subject of LB1908 CASE REPORT Single injection at the lowest dose level (0.5 million/kg) Baseline(2021-03-04) Day 45(2021-04-28) Day 90(2021-06-16) Day 180(2021-09-09) (mm) (mm) (mm) (mm) Target Lesions 1. Pelvic Lesion 132.7 119.4 113.08
Slide 52: Case Report: PK Profile
Case Report: PK Profile • CAR-T cells and CAR copies were detected from Day 2 and thereafter, with Cmax on Day 12 • CAR-T cell returned to low level on Day 45 and kept at low level on Day 58 52
Slide 53: Conclusion: LB1908
Conclusion: LB1908 • Claudin 18.2 is a very promising target for gastric cancer and pancreatic cancer • Claudin 18.2 is also a very challenging target for developing a safe but efficacious CAR-T product • LB1908 has demonstrated anti-tumor efficacy using both in vitro and in vivo models • In a curre
Slide 54: Solid Tumors: LB2101
Solid Tumors: LB2101 Solid Tumors Allogeneic Platforms
Slide 55: LB2101: The Armored CAR-T Targeting GPC-3
LB2101: The Armored CAR-T Targeting GPC-3 TARGET • GPC3 is a promising target with highly specific over-expression in solid tumors • Significantly upregulated in liver cancer (76%), lung SCC (52%), germ- cell cancers (44-100%) et al.1 TME Signal MOA/ SCIENTIFIC RATIONALE • In house developed humaniz
Slide 56: GPC3: A Well-Validated Target for Multiple Cancer Indications
GPC3: A Well-Validated Target for Multiple Cancer Indications • GPC3, an oncofetal protein, is absent in normal vital tissues. Indications %GPC3 • GPC3 has been found to be significantly upregulated in Liver Liver Cancer HCC 76% Cancer (76%), Lung SCC (52%), Germ-cell Cancers (44- Hepatoblastoma 100
Slide 57: Design of GPC3-CAR (H93) Using scFv as a Binder
Design of GPC3-CAR (H93) Using scFv as a Binder • Humanized single chain antibody fragment (scFv) • Targeting C-terminus of GPC3, unaffected by shedding of N-terminus of GPC3 • High affinity to human GPC3: 73 ± 8.7 pM (SPR) • No off-target binding in normal human tissues (TMA) • Superior in vivo ant
Slide 58: Legend's Innovative Armor Platform
Legend's Innovative Armor Platform Utilize TME signals to augment CAR-T functions Legend’s approach focuses on modifying CAR-T cells to improve intrinsic T-cell functionality in the solid tumor microenvironment. LB2101 components: • CAR: humanized scFv with optimized CAR design to target and elimina
Slide 59: The Armoring Strategy for LB2101 Markedly Improves CAR-T Functions
The Armoring Strategy for LB2101 Markedly Improves CAR-T Functions • Conditional armor activation: Improved LB2101 (H93T) expansion in the presence of GPC3 and the TME signal only • Potency: LB2101 showed tumor-free efficacy at a very low dose • Improved CAR-T expansion of H93T (LB2101) in vivo comp
Slide 60: Conclusion: LB2101
Conclusion: LB2101 • LB2101 is a novel investigational CAR-T therapy for the treatment of HCC and SCLC by specifically targeting GPC3 TME Signal • LB2101 shows superior suppression of tumor growth compared to the benchmark-based CAR-T in the HCC model • Legend’s innovative armoring strategy improves
Slide 61: Solid Tumors: LB2102
Solid Tumors: LB2102 Solid Tumors Allogeneic Platforms
Slide 62: LB2102: Legend Armored CAR-T Targeting DLL-3
LB2102: Legend Armored CAR-T Targeting DLL-3 TARGET • DLL-3, a promising target with prevalent and homogeneous expression in SCLC (~80% positive) and other neuroendocrine tumors • Minimal to no expression in normal tissues • SCLC --- market size: 15% of all lung cancers, ~270,000 new cases globally
Slide 63: Delta-like Ligand 3 (DLL3) is an Emerging Target for SCLC
Delta-like Ligand 3 (DLL3) is an Emerging Target for SCLC DLL3 in SCLC tumors DLL3 in normal tissues • Highly and homogeneously expressed • Minimal to no expression • Both on plasma membrane and in cytoplasm • Exclusive in cytoplasm DLL3 protein expression by IHC DLL3 expression in SCLC-A/N subtypes
Slide 64: LB2102: DLL3-targeting CAR-T Cell for SCLC
LB2102: DLL3-targeting CAR-T Cell for SCLC • Similar to the design of cilta-cel, two VHH binding domains targeting DLL3 were coupled TME Signal to deliver activation signal to CAR-T cells. • An armor is integrated alongside the CAR to overcome the immunosuppressive tumor microenvironment. • Preclini
Slide 65: In Vitro Pharmacology of LB2102
In Vitro Pharmacology of LB2102 • Legend proprietary biparatopic targeting strategy significantly enhanced CAR-T persistence. • Persistence of armored CAR-T cells was significantly prolonged during repetitive challenges with target cells. • The armor resisted the inhibition of cytokine production an
Slide 66: In Vivo Pharmacology of LB2102
In Vivo Pharmacology of LB2102 • The armored CAR-T showed T u m o r B u rd e n % C A R -T in P B % C A R + in liv e c e lls ( M e a n S D ) T u m o r v o lu m e (m m ) M e a n S D 2000 V e h ic l e 40 significantly superior tumor unT inhibition, when compared to 1500 C o n v e n t io n a l C A R
Slide 67: In Vivo Safety Study of LB2102
In Vivo Safety Study of LB2102 • A high dose of CAR-T cells SUBCUTANEOUS TUMOR MODEL was well tolerated in SHP-77 s.c. tumor-bearing mice; T u m o r b u rd e n B o d y w e ig h t % C A R - T in P B T u m o r v o lu m e (m m ) M e a n S D % C A R + in liv e c e lls ( M e a n S D ) B o d y w e ig
Slide 68: Conclusion: LB2102
Conclusion: LB2102 • DLL3 is a promising target expressed in SCLC but barely in normal tissues. TME Signal • Leveraging a biparatopic tandem VHH sdAb-design and TME-resistant armor strategy, LB2102 has demonstrated potent cytotoxicity, improved proliferation, persistence and tumor infiltration, and
Slide 69: Allogeneic Platforms: Non-Gene Editing LUCAR Platform
Allogeneic Platforms: Non-Gene Editing LUCAR Platform Solid Tumors Allogeneic Platforms
Slide 70: "Mainstream" Allogeneic CAR-T Approach
“Mainstream” Allogeneic CAR-T Approach Gene editing Knockout strategy • ZNF • TCRα KO to avoid GvHD • TALEN • B2M KO to evade HvG • CRISPR-Cas9 • CD52 KO to increase persistence Advantages Disadvantages • Availability of diverse • Off-target concerns gene-editing tools • Chromosomal aberration/trans
Slide 71: Legend's Unique Non-gene-editing Allogeneic Platform
Legend’s Unique Non-gene-editing Allogeneic Platform Auto-CART Gene-editing Legend Biotech Allo-CART Allo-CART TCRα/TCRβ heterodimer No TCRα/TCRβ heterodimer No TCRα/TCRβ heterodimer (functional TCR complex) (no functional TCR complex) (no functional TCR complex) 71
Slide 72: Legend's Unique Non-gene-editing Allogeneic Platform
Legend’s Unique Non-gene-editing Allogeneic Platform TRANSDUCTION GENE EDITING COMPONENTS CAR TCRα/β KO Mainstream gene- CAR …… 8-16 phenotypes editing process x TCRα/βpos+CARpos …... …... …... CAR expression TCR disruption CD52 disruption VS TCR Primary T Cells B2M disruption Other disruptions CAR
Slide 73: Safety: Disruption of the TCR Complex and Its Function
Safety: Disruption of the TCR Complex and Its Function Phenotype of LUCAR-20S Mixed Lymphocyte Reaction (MLR) A u to A llo UnT LUCAR-20S G rou p ** G rou p 10 A c tiv a tio n In te n s ity 8 TCRαβ- and 6 CAR+ 98.63% 4 TCRαβ 2 0 R R O B A A S K C C 0 α -2 to to R R C u u A T A A C R U A L CAR C to u
Slide 74: Allogeneic LUCAR-20S CAR-T Against CD20
Allogeneic LUCAR-20S CAR-T Against CD20 TARGET • CD20 is a cell surface protein on B cells with role in development and differentiation into plasma cells • Expressed in majority of mature B-cell neoplasms, including plasma cell myelomas, B-lymphoblastic neoplasms, Hodgkin lymphomas, T-cell neoplasms
Slide 75: Main Challenges of Allogeneic CAR-T Platform
Main Challenges of Allogeneic CAR-T Platform GRAFT-VERSUS-HOST DISEASE HOST-VERSUS-GRAFT CELLS GvHD HvG SAFETY PERSISTENCE (https://www.nhl-info.de/) (https://www.nhl-info.de/) Necessitates design to prevent GvHD and resist HvG at the same time. 75
Slide 76: Proof-of-concept Clinical Studies by Exploratory IIT
Proof-of-concept Clinical Studies by Exploratory IIT CAR (CD20 scFv) Targets Antigen Efficacy Gene X Prevents GvHD Safety 76
Slide 77: Study Design of LUCAR-20S
Study Design of LUCAR-20S • An open label, single arm, Phase I study to Dose Escalation （～24 pts） evaluate the safety, tolerability, and pharmacokinetics of LUCAR-20S CAR-T cells in 10M patients with relapsed or refractory CD20+ non- Accelerated Hodgkin lymphoma 30M Titration Designs • Study Objecti
Slide 78: Case Report: LUCAR-20S
Case Report: LUCAR-20S • Female/50, Follicular Lymphoma, Grade 3A, CD20（+） - Diagnosed on Feb 2018 - 4 prior lines of therapy, including anti-CD20 monoclonal antibody (Rituximab) D-7 D-6 D-5 D0 D14 D16 D20 D30 D60 D90 D180… Pre-conditioning Infusion From Day0 to day 14 Visit for Efficacy & Safety Ef
Slide 79: LUCAR-20SD Will Be Studied in Exploratory IIT
LUCAR-20SD Will Be Studied in Exploratory IIT CAR (CD20 scFv) Targets Antigen Efficacy Gene X Prevents GvHD Safety Controls HvG Gene Y Persistence with Drug Y 79
Slide 80: Safety: GvHD Assessment in Murine Model
Safety: GvHD Assessment in Murine Model Adoptive GvHD risk evaluation NCG Cell Therapy GvHD Model Days -1 0 7 14 21 28 35 42 48 60 Absence of GvHD response suggesting efficient downregulation of TCR GvHD Score Body Weight Survival 200 6 GvHD score Mean SEM Body weight (g/Group) 5 175 4 150 3 125 2
Slide 81: Resistance of LUCAR-20SD to HvG
Resistance of LUCAR-20SD to HvG Host cells and graft LUCAR-20SD cells in the MLR co-culture system HvG Strategy Pattern Without HvG Drug Combined HvG Strategy Strategy Drug Y facilitates resistance of LUCAR-20SD to HvG by host cells 81
Slide 82: Conclusion: LUCAR Platform
Conclusion: LUCAR Platform • A proprietary non-gene-editing allogeneic CAR-T platform that avoids multiple gene editing and their inherited risks of off-target effects or genotoxicity • All-in-One vector design for single step modification - High homogeneity in drug product to ensure stability and s
Slide 83: Allogeneic Platforms: CAR-NK with LGkine Armoring
Allogeneic Platforms: CAR-NK with LGkine Armoring Solid Tumors Allogeneic Platforms
Slide 84: Unique Features of CAR-NK Immunotherapy
Unique Features of CAR-NK Immunotherapy • NK cells are rapid and efficient killers of tumor cells • CAR-NK provides a promising solution to overcome TAA escape through recognition of tumor cells by multiple mechanisms • CAR-dependent killing • CAR-independent killing (e.g. NKG2D, NCRs, etc.) • Antib
Slide 85: Challenges of Allogeneic CAR-NK Therapy
Challenges of Allogeneic CAR-NK Therapy CHALLENGES • Short persistence • Long term anti-tumor activity by LGkine • Feeder cell-based NK expansion armoring processes • Feeder cell-free expansion process • Low transduction efficiency • >500 doses/batch • Fragility after cryopreservation • Robust trans
Slide 86: Key Features of CAR-NK Product
Key Features of CAR-NK Product • High purity • High transduction efficiency In v it r o C e ll K illin g A s s a y o n N C I- H 9 2 9 c e lls 100 10 4 % L y s is o f T a r g e t 80 • Robust feeder cell-free E x p a n s io n fo ld s 10 3 60 expansion process 10 2 40 20 • Strong in vitro anti-tumor 10
Slide 87: Feeder-Free Cord-Blood NK Platform
Feeder-Free Cord-Blood NK Platform • Scalable feeder free expansion, potentially 10 5 providing >500 doses/donor NK Expansion Fold • High purity: >90% NK cells, <1% T cell 10 4 contamination • Robust CAR transduction CD56 10 3 NK ~15,000 fold expansion CD3 >90% purity 100 NK MOCK 80 NK CAR % Cytotox
Slide 88: Rationally Designed LGkine Can Achieve a Balance between Efficacy and Safety
Rationally Designed LGkine Can Achieve a Balance between Efficacy and Safety • Long-term anti-tumor activity and extended animal survival were observed in animals treated with LGkine-armored CAR-NK cells 88
Slide 89: Highlights of Legend's CAR-NK Product
Highlights of Legend’s CAR-NK Product EXPANSION PERSISTENCE TUMOR TARGETING CRYOPRESERVATION EXPANSION ARMOR MULTI-TUMOR CRYO-FORMULATION METHOD APPROACH TARGETING MECHANISMS AND PROCESS • Feeder cell free • Long-term anti-tumor • Optimized CAR • Minimal loss of expansion process efficacy structure
Slide 90: Global R&D Strategy
Global R&D Strategy Institutional R&D Model that accelerates Cell Therapy Discovery and Development CORE TECHNOLOGY CAR-T >300 employees CLINICAL PLAN TCR-T One of the largest global cell therapy R&D teams NK gd - T Potential best-in-class proprietary technology PRODUCT PLATFORM Multiple Phase I pla
Slide 91: Q&A
Q&A Questions can be submitted by chat or by card
Slide 92: THANK YOU
THANK YOU @