Celyad Oncology SA · EURONEXT:CYAD
Celyad Oncology SA — Investor Day (March 2019)
48 slides from Celyad Oncology SA's investor day presentation, Mar 18, 2019
Slide 1: Pioneering innovative therapies for patients with life-threatening diseases
Pioneering innovative therapies for patients with life-threatening diseases Research & Development Day March 18, 2019 New York City
Slide 2: Today's Agenda – Building a Disruptive Pipeline in CAR-T Cell Therapy
Today’s Agenda – Building a Disruptive Pipeline in CAR-T Cell Therapy Topic Discussant Welcome & Introductions Filippo Petti Celyad’s Roadmap in CAR-T – Today, Tomorrow & Beyond Christian Homsy Operational Excellence Christian Homsy ▪ Cell Therapy Manufacturing Jean-Pierre Latere ▪ Clinical Program
Slide 3: Continuing the Advancement of CAR-T Therapies
Continuing the Advancement of CAR-T Therapies Beyond Tomorrow ▪ “Crack the code” in solid tumors with an NKG2D- Today ▪ Leverage our innovative based CAR-T therapy through well-established allogeneic approaches and novel combination including TIM for regimens to pursue ▪ Accelerate the clinical CYAD
Slide 4: Operational Excellence
Operational Excellence
Slide 5: 2018 – A Year in Review
2018 – A Year in Review Exclusive agreement First patient in for Horizon THINK trial treated April Initiation of Phase 1 Discovery’s shRNA alloSHRINK trial with drug product 2018 platform for the evaluating non-gene from amended October development of edited allogeneic manufacturing next-generation
Slide 6: Cell Therapy Manufacturing
Cell Therapy Manufacturing
Slide 7: Established Expertise in Cell Therapies Manufacturing
Established Expertise in Cell Therapies Manufacturing ▪ 15 years expertise in cell therapy ▪ Over 350 patients treated in our cardiology and oncology trials from cells manufactured in our facility in Mont-Saint-Guibert ▪ Proprietary manufacturing facility to independently improve and optimize our st
Slide 8: Capabilities Support Clinical Development and Future Product Launch
Capabilities Support Clinical Development and Future Product Launch ▪ Over 30 people in Production, Logistics, Facility, QA and QC departments to support four - six patient products per week ▪ 1,100 sq. meter facility in Mont-Saint-Guibert is equipped to supply all of Celyad’s expected clinical tria
Slide 9: Leading Manufacturing Capabilities with Two Production Areas
Leading Manufacturing Capabilities with Two Production Areas ▪ Two production areas allow for continuous cell manufacturing with no downtime for routine maintenance ▪ Scaling of our production accordingly depending on our needs ▪ Advancing in parallel both R&D efforts and clinical-stage product prod
Slide 10: Turning Research Process into Commercially Viable Manufacturing Process
Turning Research Process into Commercially Viable Manufacturing Process Process Logistics & Quality Regulatory Development Supply Chain Assurance ▪ Cryopreservation ▪ Supply of apheresis ▪ “Real-time” release ▪ Advanced therapy ▪ Mitigate patient within 48 hours ▪ Multiple personalized medicinal pro
Slide 11: Rapidly Scaling Production to Meet Current and Future Clinical Needs
Rapidly Scaling Production to Meet Current and Future Clinical Needs Over 600 Streamlined billion cells centralized logistics to produced in 2018 supply both U.S. and EU Cryopreserved 33 products Patients 94% treated in 2018 vs. manufacturing 16 in 2017 and success rate in 2018 8 in 2016 vs. 75% in
Slide 12: Clinical Program Updates
Clinical Program Updates
Slide 13: Advancing Clinical Pipeline
Advancing Clinical Pipeline Product Target Study Design Preclinical IND Submission Phase 1 Standalone THINK w/o Preconditioning Hematological malignancies and Solid tumors THINK Schedule optimization Cohort 10 / 11 w/o Preconditioning r/r AML / MDS Preconditioning CYAD-01 NKG2D DEPLETHINK with CyFlu
Slide 14: Recent Updates to Current Trials in r/r AML/MDS
Recent Updates to Current Trials in r/r AML/MDS THINK – Schedule Optimization Cohorts DEPLETHINK ▪ Cohorts will assess a more frequent dosing ▪ Dose escalation trial evaluating a single schedule of CYAD-01 including six injections injection of CYAD-01 following treatment of CYAD-01 without precondit
Slide 15: r/r AML/MDS Program – Summary of Ongoing Studies
r/r AML/MDS Program – Summary of Ongoing Studies THINK THINK – Cohort 10/11 DEPLETHINK Product (Target) CYAD-01 (NKG2D) CYAD-01 (NKG2D) CYAD-01 (NKG2D) Monotherapy ✓ ✓ Preconditioning ✓ Autologous ✓ ✓ ✓ Allogeneic Dose(s) 3x108, 1x109, 3x109 1x109 / 3x109 1x108, 3x108, 1x109 Number of injections 3 (
Slide 16: Solid Tumor Program – Summary of Ongoing Studies in mCRC
Solid Tumor Program – Summary of Ongoing Studies in mCRC THINK THINK CyFlu SHRINK alloSHRINK Product (Target) CYAD-01 (NKG2D) CYAD-01 (NKG2D) CYAD-01 (NKG2D) CYAD-101 (NKG2D) Monotherapy ✓ Preconditioning ✓ Combination ✓ (FOLFOX) ✓ (FOLFOX) Autologous ✓ ✓ ✓ Allogeneic ✓ Dose(s) 3x108, 1x109, 3x109 3
Slide 17: Building a CAR-T Pipeline Through shRNA
Building a CAR-T Pipeline Through shRNA
Slide 18: Developing a Next-Generation, Non-Gene Edited Platform for CAR-T
Developing a Next-Generation, Non-Gene Edited Platform for CAR-T ▪ Exclusive agreement with Horizon Discovery Group for the use of its shRNA technology to generate next-generation, non-gene edited allogeneic platform for CAR-T therapies ▪ Collaboration includes use of shRNA technology for additional
Slide 19: SMARTvector Lentiviral shRNA Platform
SMARTvector Lentiviral shRNA Platform SMARTvector technology mimics 1) 2) endogenous mature microRNA ▪ Based on miR-196a-2 scaffold with patented optimization ▪ Processed efficiently from a Pol II promoter allowing co-expression of a reporter (Figure 1) ▪ Maintains good functionality from the active
Slide 20: Versatility of shRNA Platform Offers Broad Approach to CAR-T Development
Versatility of shRNA Platform Offers Broad Approach to CAR-T Development Dharmacon’s SMARTvector shRNA Platform Yields Multiple Candidates CYAD-02 CYAD-200 Series Future Candidates ▪ Utilizing shRNA to target ▪ Targeting CD3ζ to ▪ Research ongoing to NKG2D ligands knockdown the TCR/CD3 investigate a
Slide 21: CYAD-02 – Next Generation NKG2D CAR-T
CYAD-02 – Next Generation NKG2D CAR-T
Slide 22: NKG2D-based CAR-T Presents Key Differentiation
NKG2D-based CAR-T Presents Key Differentiation Hexamer arrangement: Natural receptor configuration two co-stimulatory domains on the cell surface to one activatory domain Spontaneous association with 4xDAP-10 : 2xNKG2D.CD3 ζ endogenous DAP10 protein NKG2D Target Low immunogenicity Generic targeting
Slide 23: NKG2D Ligands are Expressed Transiently on Human T cells Leading to Fratricide
NKG2D Ligands are Expressed Transiently on Human T cells Leading to Fratricide which is Overcome by Antibody Blockade Academic Process Celyad Process 2015 2018 MICA/B Main NKG2D Ligands on Human T cells Can we permanently modulate the expression of NKG2D ligands in T cells? 23
Slide 24: Cell Line Screening Identified Multiple shRNAs Targeting NKG2D Ligands MICA/B
Cell Line Screening Identified Multiple shRNAs Targeting NKG2D Ligands MICA/B 24
Slide 25: Incorporating shRNA-14 into the Construct Improves the Proliferative Potential of CYAD-01
Incorporating shRNA-14 into the Construct Improves the Proliferative Potential of CYAD-01 Improved Proliferation in NKG2D Constructs Absence of Antibody Blockade CYAD-01 CYAD-02 1. Expression of shRNA-12 or shRNA-14 2. Truncated CD19 transgene serves as positive selection 25
Slide 26: Robust Increase in Persistence from CYAD-01 Construct Plus shRNA-14
Robust Increase in Persistence from CYAD-01 Construct Plus shRNA-14 Frequency of Animals with Detectable NKG2D CAR-T Cells w ith d e t e c t a b le h u m a n T c e lls (% ) 100 C Y A D -0 1 F r e q u e n c y o f a n im a ls s h R N A -1 2 s h R N A -1 4 50 0 0 20 40 60 D a y s e la p s e d 26
Slide 27: Increased Expansion and Persistence of Cells With Next-Generation, NKG2D-based CAR-T, CYAD-02
Increased Expansion and Persistence of Cells With Next-Generation, NKG2D-based CAR-T, CYAD-02 NSG Mice with Established AML Tumor Combining CYAD-01 with shRNA-14 and continued process improvement leads to development of CYAD-02 27
Slide 28: CYAD-02 Exhibits Improved Anti-tumor Activity in Established AML Model
CYAD-02 Exhibits Improved Anti-tumor Activity in Established AML Model Seven Day AML (THP-1) Model 100 V e h ic le CYAD-02 demonstrates M ock P e r c e n t s u r v iv a l C Y A D -0 1 C Y A D -0 2 improved survival 50 at dose level where CYAD-01 has minimal activity (three doses of 0 3 x 106 cells)
Slide 29: No Overt Disturbance of the Transcriptome Through shRNA Expression
No Overt Disturbance of the Transcriptome Through shRNA Expression CYAD-02 vs CYAD-01 Volcano Plots 12 MICB 12 CD4 CD8 10 10 MICB -lo g 1 0 (p -v a lu e ) -lo g 1 0 (p -v a lu e ) 8 8 6 6 4 4 2 2 0 0 -2 -1 0 1 2 -2 -1 0 1 2 lo g 2 F C ( C Y A D - 0 2 v s . C Y A D - 0 1 ) lo g 2 F C ( C Y A D - 0 2
Slide 30: Summary and Next Steps for CYAD-02
Summary and Next Steps for CYAD-02 ▪ Single shRNA is able to modulate the expression of MICA/B which translates to encouraging increase in in vivo engraftment and anti-tumor activity ▪ Generate additional preclinical proof-of-concept data for program throughout 2019 ▪ Submission of investigational n
Slide 31: shRNA Platform for Allogeneic CAR-T
shRNA Platform for Allogeneic CAR-T
Slide 32: Multiple Targets to Generate Allogeneic T-cells
Multiple Targets to Generate Allogeneic T-cells TCRα (TRAC) is a common target for TCR complex is gene edited approaches responsible for Graft-versus- Host Disease (GvHD) Knockdown of specific CD3 components (i.e. CD3ε) could also As such, lead to loss of the TCR at cell surface elimination of the T
Slide 33: Initial Screening of shRNA Targeting CD3 in Jurkat T-cells
B . C D 3 m R N A f o ld c h a n g e o v e r 1 .5 C T R (t C D 1 9 ) 1 .0 Initial Screening of shRNA Targeting CD3 in Jurkat T-cells T C R / T C R / 0 .5 Specificity D . of Targeting Individual CD3 0 .0 E . Reduction of T-Cell Response Components Through shRNA ) 3 3 9 1 D D D C C C A A (
Slide 34: Comparison of shRNA vs. Gene Editing
Comparison of shRNA vs. Gene Editing ▪ To compare in preclinical models the ability of shRNA to modulate the expression levels of the TCR complex from the cell surface of T-cells with that of gene editing technology, we developed a CRISPR control knockout of the CD3ζ to mimic our shRNA approach ▪ Bo
Slide 35: shRNA vs. CRISPR: Equivalent Knockdown of TCR
shRNA vs. CRISPR: Equivalent Knockdown of TCR Cell Surface TCR Complex Intensity of TCRα/β TCR Stimulation Assay 8 0 0 0 1 .0 0 .8 6 0 0 0 IF N (n g / m l) C D 2 5 M F I 0 .6 C T R (tC D 4 0 0 0 s h R N A C D 0 .4 C R IS P R C 8 0 0 0 1 .0 2 0 0 0 0 .2 8 0 0 0 1 .0 0 .8 8 0 0 0 6 0 0 0 0 1 .0 0 .0
Slide 36: In Vivo Protection of GvHD by shRNA targeting CD3ζ
In Vivo Protection of GvHD by shRNA targeting CD3ζ Survival Persistence Mean Weight 28 100 26 P e r c e n t s u r v iv a l 24 w e ig t h ( g ) 22 50 tC D 1 9 C T R T c e lls ( n = 2 2 ) 20 s h R N A C D 3 T c e lls ( n = 2 3 ) tC D 1 9 C T R T c e lls (n = 2 2 ) < 50% of a n im a ls a liv e s h R
Slide 37: Summary of shRNA Platform Benefits
Summary of shRNA Platform Benefits ▪ Differentiated methodology to knockout the TCR complex in allogeneic CAR-T therapies compared to gene editing techniques ▪ Ability to knockdown the majority but not all of the TCR complex versus gene edited approaches allows for increased persistence of shRNA-bas
Slide 38: CYAD-200 Series of Allogeneic CAR-Ts
CYAD-200 Series of Allogeneic CAR-Ts
Slide 39: Trio of Disruptive, First-in-Class, Non-Gene Edited Allogeneic CARs
Trio of Disruptive, First-in-Class, Non-Gene Edited Allogeneic CARs CYAD-200 Series CYAD-211 CYAD-221 CYAD-231 BCMA CAR-T CD19 CAR-T Dual specific for multiple myeloma for B-cell malignancies NKG2D x Undisclosed CAR-T ▪ Evaluate shRNA approach ▪ Despite multiple marketed ▪ Currently evaluating with
Slide 40: Anti-tumor Activity of BCMA-CAR.shRNA CD3z in Preclinical Model
Anti-tumor Activity of BCMA-CAR.shRNA CD3z in Preclinical Model KMS.11 Multiple Myeloma Model Day 21 Vehicle Mock BCMA-CAR.shRNA CD3z demonstrates tumor control .shRNA CD3z BCMA-CAR as early as one week after single injection of 10 x 10 6 CAR T cells without any signs of toxicity 40
Slide 41: CYAD-200 Series Strategically Positioned to Leapfrog the Competition in Allogeneic CAR-T
CYAD-200 Series of CAR-T Candidates is Strategically Positioned to Leapfrog the Competition in Allogeneic CAR-T Development ▪ shRNA platform provides us with a next-generation, potential best-in-class allogeneic approach to CAR-T development ▪ Single step gene engineering combining inhibition of TCR
Slide 42: "All-in-One Vector" Approach
“All-in-One Vector” Approach
Slide 43: "All-in-One Vector" Approach Provides Flexibility and Versatility
“All-in-One Vector” Approach Provides Flexibility and Versatility to Design Novel CAR-T Therapies ▪ Ability to include several T cell engineering steps in one single step ▪ Efficiencies across all segments of R&D as well as cell manufacturing ▪ Leverages experience and expertise gained to date from
Slide 44: Final Remarks and Q&A
Final Remarks and Q&A
Slide 45: Updated CAR-T Therapy Pipeline
Updated CAR-T Therapy Pipeline Product Target Study Design Preclinical IND Submission Phase 1 Standalone w/o THINK Hematological malignancies and Solid tumors Preconditioning THINK Schedule optimization r/r AML / MDS AUTOLOGOUS Cohort 10/11 w/o Preconditioning CYAD-01 NKG2D DEPLETHINK Preconditionin
Slide 46: Upcoming Milestones
Upcoming Milestones Second Quarter 2019 Second Half 2019 First Half 2020 ▪ Updated data from dose level 3 ▪ Additional data from Cohort 11 of ▪ Submission of IND for next- and initial data from Cohort 10 of THINK trial as well as full data generation NKG2D CAR-T THINK trial evaluating CYAD-01 from D
Slide 47: Continuing the Advancement of CAR-T Therapies
Continuing the Advancement of CAR-T Therapies Beyond Tomorrow ▪ “Crack the code” in solid tumors with an NKG2D- Today ▪ Leverage our innovative based CAR-T therapy through well-established allogeneic approaches and novel combination including TIM for regimens to pursue ▪ Accelerate the clinical CYAD
Slide 48: Thank you
Thank you