Cartesian Therapeutics, Inc. · NASDAQ:RNAC
Cartesian Therapeutics — Selecta Biosciences — Jefferies Gene Therapy Summit 2018
27 slides from Cartesian Therapeutics's conference presentation, Sep 27, 2018
Slide 1: Jefferies Gene Therapy Summit September 2018
Jefferies Gene Therapy Summit Nasdaq: SELB 27 September 2018
Slide 2: Safe Harbor / Disclaimer
Safe Harbor / Disclaimer Any statements in this presentation about the future expectations, plans and prospects of Selecta Biosciences, Inc. (“the company”), including without limitation, statements regarding the potential impact of adaptive immunity on AAV gene therapy, the potential benefits of re
Slide 3: Immunogenicity is Now Recognized as a Serious Challenge for Biologic Therapies
Immunogenicity is Now Recognized as a Serious Challenge for Biologic Therapies I M M U N O G E N I C I T Y ’ S I M P A C T COMPROMISED EFFICACY SAFETY RISK UNPREDICTABLE RESPONSE Anti-drug antibodies (ADAs) Hypersensitivity reactions can Changed PK/PD through neutralize therapeutic benefit impact pa
Slide 4: The Promise of Gene Therapy
The Promise of Gene Therapy • Remarkable progress • Potential life-transforming benefit • Durable responses in adult patients 4
Slide 5: Potential Impact of Adaptive Immunity on AAV Gene Therapy
Potential Impact of Adaptive Immunity on AAV Gene Therapy Humoral immunity Cellular immunity Neutralizing antibodies B cell CD8+ cytolytic T cell AAV Prevention of Elimination of AAV transduction transduced cells 5
Slide 6: Appearance of AAV-Specific CD8 T Cells Correlates with Liver Enzyme Elevation
Appearance of AAV-Specific CD8 T Cells Correlates with Liver Enzyme Elevation and Loss of Transgene Expression in Humans Hemophilia B patient administered AAV- Factor IX gene therapy Capsid-specific CD8+ T cell responses Nathwani et al., N Engl J Med. 2011 weeks 6
Slide 7: Neutralizing Antibodies Inhibit AAV Transduction
Neutralizing Antibodies Inhibit AAV Transduction • Neutralizing antibodies - Form after first exposure to AAV - Titers as low as 1:5 can inhibit AAV transduction - Persist for years after exposure - Cross react with other AAV serotypes - Prevent re-dosing Baseline AAV2 Nab titer AAV2 Nab titer AAV8
Slide 8: Potential Benefits of Re-dosing AAV Gene Therapy
Potential Benefits of Re-dosing AAV Gene Therapy AAV AAV • Increase percentage of patients Therapeutic target zone that achieve therapeutic benefit Dose titration without risk of over-dosing Activity • Improve enrollment in clinical trials Time AAV AAV • Restore therapeutic expression Therapeutic ta
Slide 9: Potential Benefits of Re-dosing AAV Gene Therapy
Potential Benefits of Re-dosing AAV Gene Therapy AAV AAV Neutralizing antibodies Therapeutic target zone Dose titration Activity Formation of neutralizing Time antibodies after first administration of AAV gene AAV AAV Neutralizing antibodies therapy may prevent re-dosing Therapeutic target zone Resc
Slide 10: Need for Repeat Dosing of Systemic Gene Therapy in Pediatric Patients
Need for Repeat Dosing of Systemic Gene Therapy in Pediatric Patients Liver weight in children • Genetic metabolic diseases often manifest early in 900 childhood 800 • Gene therapy would benefit children the most, as 700 irreversible damage can occur if disease is not controlled 600 500 • However AA
Slide 11: Vector Dilution and Loss of Transgene Expression after AAV Gene Therapy in Neonatal Mice
Vector Dilution and Loss of Transgene Expression after AAV Gene Therapy in Neonatal Mice Vector Genomes Liver Weight 8 7 6 5 genomeVG/diploid 4 2d 1wk 2wk 1mo 2mo 17mo 3 2 Transgene Expression 1 Liver weight doubling weight Liver 0 WT 1.5d 1 2 3 4 MUT + AAV-hUgt1a1 weeks Age % Ugt1a1activity% 2d 1wk
Slide 12: Notable Early Successes in AAV Gene Therapy
Notable Early Successes in AAV Gene Therapy Liver-targeted gene therapy indications • Hemophilia A Hemophilia A • Hemophilia B • Methylmalonic acidemia Adults • Ornithine transcarbamylase disease Hemophilia B • Crigler Najjar Inherited • Primary hyperoxaluria type 1 Retinal • Wilson disease Disease
Slide 13: ImmTOR Technology for Mitigating Immunogenicity
ImmTOR Technology for Mitigating Immunogenicity • Rapamycin • PLA + • PLA-PEG • Biologic • Induction of tolerogenic dendritic cells and antigen-specific regulatory cells • Mitigation of anti-drug antibodies • Robust and scalable GMP manufacturing 13
Slide 14: Leveraging Natural Disposition of Nanoparticles to Deliver Instructions to the Immune System
Leveraging Natural Disposition of Nanoparticles to Deliver Instructions to the Immune System Spleen I.V. Injection Spleen harvested 24 hr after I.V. (6hr post-injection) Injection of fluorescent NPs . . SVP . Macrophages . Dendritic cells B cells SVP Antigen 14
Slide 15: Dendritic Cells at the Crossroads of Immune Stimulation and Immune Tolerance
Dendritic Cells at the Crossroads of Immune Stimulation and Immune Tolerance SVP-Rapamycin Antigen Lymph Node Dendritic cell TOLERANCE STIMULATION Helper Naïve T cell T cell Induction of tolerogenic DC B cell Naïve T cell Regulatory T cell Prevention of Anti-Drug Immune suppression mediated Antibo
Slide 16: SVP Technology for ADA Mitigation
SVP Technology for ADA Mitigation Targeted Enzymes Viral Vectors Immunotoxins Antibodies IMMUNE TOLERANCE SVP Encapsulating Nanoparticle Encapsulated Rapamycin PLA+PLA-PEG 16
Slide 17: SVP Technology for ADA Mitigation
SVP Technology for ADA Mitigation Biologic Citation Status Pegsiticase Kishimoto et al., 2016, Nature Nanotech Phase 2 clinical trial LMB-100 Mazor et al., 2018, PNAS Phase 1 clinical trial AAV Meliani et al., Nature Commun, in press Preclinical development Humira Kishimoto et al., 2016, Nature Nano
Slide 18: SEL-212 Phase 1b Trial of SVP-Rapamycin Combined with Pegsiticase in Hyperuricemia
SEL-212 Phase 1b Trial of SVP-Rapamycin Combined with Pegsiticase in Patients with Hyperuricemia 1 0 No effect of SVP- 8 0.03, 0.1, 0.3 mg/kg 6 Rapamycin on on SVP-Rapamycin only 4 serum uric acid levels 2 N = 15 0 1 0 Loss of control over 8 N = 5 0.4 mg/ kg Pegsiticase only 6 serum uric acid 4 leve
Slide 19: Gene Therapy
Gene Therapy
Slide 20: SVP-Rapamycin Enables Successful Vector Re-Administration of AAV Gene Therapy
SVP-Rapamycin Enables Successful Vector Re- Administration of AAV Gene Therapy Vector Empty Nanoparticle Empty Nanoparticle Federico Mingozzi, Ph.D. AAV8-Luciferase AAV8-Factor IX Head of Immunology and Liver Gene Transfer Unit Day 0 21 53 Genethon, France SVPSVP-Rapamycin SVP-Rapamycin Currently CS
Slide 21: Repeat Administration of AAV Targets Additional Hepatocytes in the Liver
Repeat Administration of AAV Targets Additional Hepatocytes in the Liver Repeat administration of AAV with SVP-Rapamycin can target different hepatocytes • 1st dose: AAV8-GFP + SVP • 2nd dose: AAV8-UGT1A1 + SVP 21 Data generated in collaboration with Dr. Federico Mingozzi, Genethon
Slide 22: Antigen-specificity of SVP-Rapamycin Effects
Antigen-specificity of SVP-Rapamycin Effects Treatment Challenge AAV8 + SVP[Rapa] AAV8 or AAV5 AAV8 + SVP[Empty] Day 0 Day 21 AAV8 Challenge AAV5 Challenge 22 Melani et al, Nature Commun, in press
Slide 23: Demonstration of the Role of Regulatory T Cells
Demonstration of the Role of Regulatory T Cells Effect can be Transferred to a Recipient T Reg Depletion Negates Effect AAV8-Luc +/- SVP AAV8-Luc +/- SVP PRIME CHALLENGE DONOR Transfer splenocytes Day 0 14 AAV8-hFIX Day 0 19 20 21 32 RECIPIENT Anti-CD25 Treg Depletion Day 0 1 28 Anti-AAV8 IgG levels
Slide 24: SVP-Rapamycin Blocks AAV8-Specific T Cell Response
SVP-Rapamycin Blocks AAV8-Specific T Cell SVP-RapamycinResponse Inhibits T Cell Responses SVP-Rapamycin or Empty Nanoparticle AAV8 Day 0 Capsid-specific CD8 T cell Splenic T cells Liver Infiltrates ) t s 1 0 0 l 5 C l * e c ) ( 4 8 0 s T l s l l c e e i 3 c f v i 6 0 e 6 c 0 L e 2 1 / p 4 0 A s
Slide 25: Opportunities for Clinical POC in Gene Therapy
Opportunities for Clinical POC in Gene Therapy • Proprietary programs - Methylmalonic acidemia - Ornithine transcarbamylase deficiency • Spark Therapeutics - Licensed SVP-Rapamycin for hemophilia A, as well as exclusive options for up to four additional undisclosed genetic targets • Genethon and the
Slide 26: Immune Tolerance Pipeline
Immune Tolerance Pipeline Indication Description Preclinical Phase 1 Phase 2 Proprietary ADA Mitigation Programs SVP-Rapamycin co-administered with Chronic Severe Gout pegsiticase (SEL-212) Mesothelioma & SVP-Rapamycin co-administered with Pancreatic Cancer LMB-100 Methylmalonic SVP-Rapamycin co-adm
Slide 27: Thank You
Se SELECTA osciences Thank You
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