Synlogic Inc · OTC:SYBX
Synlogic — SITC 2018
63 slides from Synlogic's conference presentation, Nov 13, 2018
Slide 1: Development of Synthetic Biotic Medicines in Oncology
Development of Synthetic Biotic™ Medicines in Oncology Designed for life © 2018 Synlogic, Inc. All rights reserved. Aoife Brennan, M.B., B.Ch., President and CEOSITC 2018- Washington, DCNovember 10th, 2018
Slide 2: Forward Looking Statements
Forward Looking Statements This presentation contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in
Slide 3: Agenda
12:30 pm - 12:40 pm Introductions and intro to Synlogic platform and approach Aoife Brennan, MB, ChB President & CEO, CMO, Synlogic Inc.12:40 pm - 12:55 pm Unmet medical need in solid tumor immunotherapy Filip Janku, MD, PhD MD Anderson Cancer Center12:55 pm - 1:10 pm Role of Type I IFN in tumor imm
Slide 4: Synthetic Biotic Medicines: A Novel Class of Living Medicines
SyntheticDesigned genetic circuits Degradation of disease-causing metabolitesProduction of therapeutic molecules BioticBacterial chassisNon-pathogenicAmenable to genetic manipulation © 2018 Synlogic, Inc. All rights reserved. Synthetic BioticTM Medicines: A Novel Class of Living Medicines 4 Programm
Slide 5: Platform Breadth and Potential: Pipeline Focused on Three Therapeutic Areas
Inborn Errors of MetabolismMetabolic DiseaseImmunomodulation Immuno-Oncology 1 Lead Discovery Lead Optimization IND-Enabling Studies Phase I Phase II Hyperammonemia - Urea Cycle Disorder SYNB1020 Phenylketonuria SYNB1618 Organic Acidemias Maple Syrup Urine Disease Inflammatory Bowel Disease Immuno-O
Slide 6: Bacteria Recognized as Earliest Immunotherapy
Nature often gives us hints to her profoundest secrets, and it is possible that she has given us a hint in which, if we will but follow, may lead us on to the solution of this difficult problem.Dr. William B. ColeyImmuno-Oncology Pioneer “ ” © 2018 Synlogic, Inc. All rights reserved. 6 Bacteria Reco
Slide 7: Synlogic Vision for Immuno-Oncology
© 2018 Synlogic, Inc. All rights reserved. 7 Expand the benefits of immunotherapy broadly across tumor types Synlogic Vision for Immuno-Oncology For indications where immune checkpoint inhibitors are indicated, only 13-45% of patients respond Other tumor types show little-to-no response to checkpoin
Slide 8: Unmet medical need in solid tumor immunotherapy
Unmet medical need in solid tumor immunotherapy Filip Janku, MD, PhDAssociate ProfessorClinical & Translational Research Center Medical Director Investigational Cancer Therapeutics(Phase I Clinical Trials Program)MD Anderson Cancer CenterHouston, TX
Slide 9: FDA-approved immune checkpoint inhibitors
Ipilimumab Melanoma FDA- approved aaa ARTS Small cell lung cancer Immune oo Nivolumab Classical Hodgkin lymphoma ‘Squamous cell carcinoma of the head and neck Checkpoint aoe Hepatocellular carcinoma =p: | n h l b ito Ss Mismatch repair deficient and microsatellite instability high metastatic colorec
Slide 10: Response rates to checkpoint inhibitors in approved indications
Response rates to checkpoint inhibitors in approved indications Melanoma Pembrolizumab: RR ~ 30% Nivolumab/ipilimumab: RR ~ 50%Non-small lung cancer Pembrolizumab: RR ~ 20%-40%Nivolumab: RR ~ 20%SCC of head and neck Pembrolizumab: RR ~ 18%Nivolumab: RR ~ 13% Urothelial cancer Pembrolizumab: RR ~ 21%
Slide 11: Classification by tumor immune phenotype in urothelial cancers
Classification by tumor immune phenotype in urothelial cancers Immune excluded (CD8 trichrome stain) Mariathasan S. Nature 2018
Slide 12: Immunotherapy: unmet need
Immunotherapy: unmet need MSI-H: ~5% of mCRC Siegel CA J Cancer Clin 2018 Ovarian cancerSoft tissue sarcomasGliomaMyeloma
Slide 13: Predictive factors for response to immune checkpoint inhibitors
Predictive factors for response to immune checkpoint inhibitors PD-L1 expression TMB MSI-H/dMMR
Slide 14: Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle
Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle Chen DS. Immunity 2013
Slide 15: Mechanisms of immunoresistance
Mechanisms of immunoresistance Syn Lancet Oncol 2017Blank Science 2016
Slide 16: Converting Cold Tumors into Hot
Converting Cold Tumors into Hot Haanen Cell 2017
Slide 17: Patient with MPNST with spontaneous remission after infection
Patient with MPNST (sarcoma) with spontaneous remission after prolonged infection with coagulase negative staphylococcus and Klebsiella Pneumoniae January 2013 May 2013 September 2013 Prolonged infection with bacteremia January to February 2013
Slide 18: Anticancer activity of intratumor Clostridium Novyi-NT
Anticancer activity of single intratumor injection of Clostridium Novyi-NT Janku CRI-CMIT-EATI-AACR 2018
Slide 19: Cytokine response after Clostridium Novyi-NT injection
Cytokine response after single intratumor injection of Clostridium Novyi-NT Janku CRI-CMIT-EATI-AACR 2018
Slide 20: Antitumor Activity of STING
Antitumor Activity of STING Barber Nat Rev Immunol 2015
Slide 21: Phase I: Intratumor STING agonist MK-1454 safety
Harrington ESMO 2018 Phase I: Intratumor STING agonist MK-1454 +/- pembrolizumab Phase I: Accelerated Titration Design -> modified Toxicity Probability IntervalEndpointsPrimary: safety, doseSecondary: PK/PDExploratory: objective responseDLTs:Monotherapy (26 patients): G3 vomiting (1)Combination (25
Slide 22: MK-1454 efficacy
Harrington ESMO 2018 Phase I: Intratumor STING agonist MK-1454 +/- pembrolizumab EFFICACYMonotherapyMyoepitehlial carcinoma > - 30% (not confirmed as PR)2 patients with shrinkage of injected lesionsCombinationPartial response: 6 (TNBC, 1; HNSCC, 3; ATC, 2)Shrinkage of injected and noninjected lesion
Slide 23: MIW815 STING agonist data
SITC 2018: MIW815 STING agonist 41 pretreated patients with solid tumors or lymphomasNo DLTsThe most common AEs: pyrexia (7; 17.1%), injection site pain (6; 14.6%), headache (6; 14.6%). Grade 3/ 4 AEs: increased lipase (2; 4.9%), elevatedamylase, tumor pain, dyspnea, respiratory failure,and injectio
Slide 24: STING agonists in the clinic
STING agonists in the clinic MK-1454: early data for monotherapy and combination with pembrolizumab presented at ESMO 2018MIW815: early data for monotherapy presented at SITC 2018MK-2118: clinical trial ongoing (monotherapy and combination with pembrolizumab)
Slide 25: Conclusions
Conclusions Immunotherapy with immune checkpoint inhibitors can be effective in subsets of patients with melanoma, lung cancer and other tumor typesImmunotherapy with immune checkpoint inhibitors has not shown enough activity resulting in FDA approval in many common cancers including breast cancer,
Slide 26: Role of type I IFN in tumor immune recognition and therapy
Role of type I IFN in tumor immune recognition and therapy Dmitriy Zamarin MD PhDAssistant Attending PhysicianTranslational Research DirectorGynecologic Medical Oncology ServiceImmunotherapeutics ServiceMemorial Sloan Kettering Cancer Center
Slide 27: Type I IFN: the first cytokine
Type I IFN: the first cytokine Alick Isaacs Jean Lindenmann Isaacs, A., and Lindenmann, J., Proc. Roy. Soc., B, 147, 258 (1957)
Slide 28: Functions of type I IFN in infection
Functions of type I IFN in infection Ivashkiv et al. Nat Rev Immunol 2013
Slide 29: Cross-talk between type I IFN and adaptive immunity
Cross-talk between type I IFN and adaptive immunity Trinchieri G, JEM 2010.
Slide 30: Type I IFN transcripts correlate with T cell infiltration
Type I IFN- related transcripts correlate with T cell infiltration in tumors Fuertes M.B. et al., JEM. 208:2005-16 (2011)
Slide 31: Type I IFN signature and clinical benefit from ipilimumab
Type I IFN signature is associated with clinical benefit from ipilimumab in melanoma Chiappinelli et al., Cell 2015
Slide 32: Type I IFN pathway essential for immunotherapy efficacy
Type I IFN pathway is essential for the efficacy of cancer immunotherapy a. Zamarin D, Wolchok JD, Allison JP. Sci Transl Med. 2014 5:226ra
Slide 33: Mechanisms of activation of type I IFN pathway
Mechanisms of activation of type I IFN pathway
Slide 34: TLR & NLR signaling pathways
Kettering t Antibodies & Inhibitors Reporter plasmids Ligand screeni i ‘Agonist & Antagonists reporter cell lines Genes & shRNAS The TRUSTED SOURCE for all your TLR & NLR needs @invivoGen
Slide 35: CLR, RLR & CDS Signaling Pathways
CLR, RLR & CDS Signaling Pathways ‘Agonist S Antagonists | Antibodies & Inhibitors n Kettering @invivoGen — The TRUSTED SOURCE forall your CLR, RLR & CDS needs | remrerceines
Slide 36: STING pathway required for immune recognition of tumors
STING pathway is required for immune recognition and elimination of tumors. Woo …. Gajewski. Immunity 2015.
Slide 37: Therapeutic strategies to target type I IFN pathway in cancer
Therapeutic strategies to target type I IFN pathway in cancer TLR agonistsSTING agonistsVirusesBacteriaEngineered viruses and bacteria
Slide 38: Development of a STING Agonist-producing Synthetic Biotic Medicine
Development of a STING Agonist-producing Synthetic Biotic™ Medicine to Activate Innate and Adaptive Immunity and Drive Antitumor Immune Responses Designed for life © 2018 Synlogic, Inc. All rights reserved. Jose M. Lora, PhDVice President, ResearchSITC 2018- Washington, DCNovember 10th, 2018
Slide 39: A Tumor Can Evade Multiple Aspects of the Cancer-Immunity Cycle
A Tumor Can Evade Multiple Critical Aspects of the Cancer-Immunity Cycle . 39 Killing Recognition Infiltration Antigen release Presentation Priming and activation T cell trafficking © 2018 Synlogic, Inc. All rights reserved. Insufficientactivity/proliferation Immuno-suppression Insufficient traffick
Slide 40: Rational Design of Immunostimulatory Mechanisms in a Bacterial Chassis
40 Prime for Tumor Antigen-Specific VaccinationChassis effectProduce lytic factorsProduce agonists for immune cell activation Promote TraffickingChassis effectProduce cytokines/chemokines Promote and Sustain Immune Activation / ProliferationProduce Immunostimulatory MoleculesPromote Immune Cell Surv
Slide 41: Synthetic Biotic Medicines Attributes
© 2018 Synlogic, Inc. All rights reserved. 41 Synthetic Biotics Medicines Attributes Platform Flexibility to Maximize Efficacy, Control, and Safety EFFICACY DRIVERS CONTROL SAFETY Sustained Payload Delivery: Persistence in TMEMultiple Mechanisms: Large gene insertion capacityCellular Bioreactors: En
Slide 42: Intra-tumoral Injection: Tumor Colonization Without Leakage
Elicits innate responses (e.g., IL-6, TNFα) in the tumor, not in circulation Intra-tumoral Injection of Synthetic Biotic Chassis: Tumor Colonization Without Leakage; Local Innate Immunity © 2018 Synlogic, Inc. All rights reserved. 42 Robust proliferation in tumor.No significant leakage to tissues Su
Slide 43: SYNB1891: Dual Innate Immune Activator
Synthetic biology applied to IO programs to confer activities for efficacy and control for safetySYNB1891 designed as a dual innate immune activator: Combined benefit of bacterial chassis and STING agonistdacA gene: Integrated into the genome under the control of inducible promoter (Pfnr) to produce
Slide 44: Dual Innate Immune Activator
Dual Innate Immune Activator © 2018 Synlogic, Inc. All rights reserved. 44 TUMOR CDA-STINGActivation 1 SYN-STING Naked STING Agonist Gram-negative BacteriaE.Coli Nissle SYNB1891 TLR4 IFN-b1 Type 1 IFN P IRF3 Phagosome CDAC-di-AMP STING Bacterial TLR/MyD88 Signaling TNF, others 4 CYTOSOL NUCLEUS
Slide 45: SYNB1891 Leverages Natural Phagocytic Activity of APCs
SYNB1891 Leverages Natural Phagocytic Activity of Antigen Presenting Cells © 2018 Synlogic, Inc. All rights reserved. 45 CDA Agonizes STING in Natural Context
Slide 46: In Vitro Characterization of SYNB1891
In Vitro Characterization of SYNB1891 SYNB1891 SYN STING Agonist Not Released to Extracellular Space Dose-dependent Activity in Mouse APCs © 2018 Synlogic, Inc. All rights reserved. 46 EC: ExtracellularIC: Intracellular SYNB1891-PT1 IC SYNB1891-PT1 EC SYN EC SYN IC
Slide 47: In Vitro Characterization: Interferon Production Across Human STING Alleles
© 2018 Synlogic, Inc. All rights reserved. In Vitro Characterization of SYNB1891 Interferon Production Across Multiple Human STING Alleles Greater than Naked STING AgonistAdditional Proinflammatory Pathways Engaged 47 Control SYNB1891-PT2 Naked Agonist Reporter THP-1 Primary DCs Synthetic Biotic Sol
Slide 48: In Vivo Bacterial Kinetics of SYNB1891
In Vivo Bacterial Kinetics of SYNB1891 Restricted to Tumor and Cleared Quickly 1x107 Dose 1x108 Dose 1x109 Dose 48 © 2018 Synlogic, Inc. All rights reserved. Tumor Homogenate (CFU, CDA, IFNb) BF16-F10 tumors ~200mm3,Randomize groups Tumor Blood
Slide 49: Pharmacodynamic Characterization of SYNB1891
Pharmacodynamic Characterization of SYNB1891 Dose-dependent Increases in Tumoral IFNβ and Other Innate Immune Markers Saline SYNB1891 (1e7 CFU) SYNB1891 (1e8 CFU) SYNB1891 (1e9 CFU) 49 © 2018 Synlogic, Inc. All rights reserved. Administration of SYNB1891 Results in Dose-dependent Increase in Tumoral
Slide 50: In Vivo Characterization: Anti-tumor Activity as a Single Agent
d1 108 or 109 cfu, i.t. (SYNB1891) B16-F10 tumors ~100 mm3, randomize groups d7 d4 d18 In Vivo Characterization of SYNB1891 d1 109 cfu, i.t. (SYNB or SYNB1891) B16-F10 tumors ~100 mm3, randomize groups d7 d4 d21 SalineSYNBSYNB1891 Study Day Dose Dose Delivers Anti-tumor Activity as a Single Agent 50
Slide 51: Dose-dependent Anti-tumor Activity of Prototype Strain
© 2018 Synlogic, Inc. All rights reserved. In Vivo Characterization of SYNB1891 Control SYN-STING 1e7 SYN-STING 5e7 SYN-STING 1e8 21 d1 107, 5x107 or 108 cfu, i.t. (SYNB1891-PT1) A20 tumors ~100 mm3, randomize groups d7 d4 d18 ControlSYNB1891-PT1 (1 x 107) SYNB1891-PT1 (5 x 107)SYNB1891-PT1 (1 x 108
Slide 52: Prototype Strain Leads to Systemic Anti-tumor Immunity
In Vivo Characterization of SYNB1891 SalineSYNB1891-PT1Naïve Control Re-challenge SYNB1891-PT1 dose SYNB1891 Prototype Strain Leads to Systemic Anti-tumor Immunity © 2018 Synlogic, Inc. All rights reserved. 22 Day on Study Tumor Volume (mm3) Saline SYNB1891-PT1 Naïve Control
Slide 53: Generation of Tumor Antigen-specific T Cells
In Vivo Characterization of SYNB1891 Day 2 Day 9 Saline SYNB SYNB1891-PT2 Gated on live CD8+ T cells H2-kb (Trp2) CD8α d1 109 cfu, i.t..YN or SYN-STING) B16-F10 tumors ~100 mm3, randomize groups d2 d4 d9 Tumor Draining LN (Flow) (SYNB or SYNB1891-PT2) SYNB1891 Prototype Strain Leads to Generation of
Slide 54: Promise Over Other Approaches / Progress Towards the Clinic
© 2018 Synlogic, Inc. All rights reserved. 54 Promise Over Other Approaches STING Agonism in Natural ContextActivation of Multiple Innate Immune PathwaysLow Systemic Risk Progress Towards the Clinic Tumor Colonization without LeakageEnhanced Activity vs. Naked STING AgonistIntracellular Activation o
Slide 55: Next Steps
© 2018 Synlogic, Inc. All rights reserved. 55 NEXT STEPSIND-Enabling Studies On-goingIND Submission 2H19 Dual Innate Immune Activator SYNB1891 TUMOR LYMPH NODE Systemic Tumor Antigen Specific Immunity Locally Inflame the TME
Slide 56: Pipeline of Synthetic Biotic Effectors Poised to Deliver
© 2018 Synlogic, Inc. All rights reserved. 56 Prime for Tumor Antigen-Specific Vaccination Promote TraffickingChassis effectCXCL10Hyaluronidase Promote and Sustain Immune Activation / ProliferationIL-15; IL-12Arg Production4-1BBLOX40L Relieve ImmunosuppressionKyn ConsumptionAde ConsumptionαPD-1 scFv
Slide 57: Q&A
Designed for life © 2018 Synlogic, Inc. All rights reserved. Aoife Brennan, M.B., B.Ch., President and CEOJose M. Lora, PhDVice President, ResearchSITC 2018- Washington, DCNovember 10th, 2018 Q&A Development of Synthetic Biotic™ Medicines in Oncology
Slide 58: Promise Over Other Approaches
© 2018 Synlogic, Inc. All rights reserved. 58 Promise Over Other Approaches STING Agonism in Natural ContextActivation of Multiple Innate Immune PathwaysLow Systemic Risk Progress Towards the Clinic Tumor Colonization without LeakageEnhanced Activity vs. Naked STING AgonistIntracellular Activation o
Slide 59: Broad Ambitions in Immuno-Oncology
© 2018 Synlogic, Inc. All rights reserved. 59 Broad Ambitions in Immuno-Oncology Vision: Expand and Exceed the Effect of Cancer Immunotherapies SYNB1891 DISCOVERY PORTFOLIO COMBINATIONS HARNESS THE MICROBIOME ORAL INTRATUMORAL
Slide 60: © 2018 Synlogic, Inc. All rights reserved.
© 2018 Synlogic, Inc. All rights reserved.
Slide 61: Table of Synthetic Biotic Strains
© 2018 Synlogic, Inc. All rights reserved. 61 Table of Synthetic Biotic Strains Strain Genetic Content SYN Un-engineered E. coli Nissle:Abx+ SYNB DAP/Thy dln EcN (no dacA insert):Abx+ SYNB1891-PT1 DAP dln EcN:dacAplasmid:FnR-inducible:Abx+ SYNB1891-PT2 DAP/Thy dln EcN:dacAintegrated:FnR-inducible:Ab
Slide 62: Pharmacodynamic Characterization of SYNB1891
Pharmacodynamic Characterization of SYNB1891 IL-6 GM-CSF C-di-AMP IFNb Administration of SYNB1891 Results in Dose-dependent Increases in Tumoral CDA, Cytokines Saline SYNB1891 (1e7 CFU) SYNB1891 (1e8 CFU) SYNB1891 (1e9 CFU) Production in Tumor Tissue pg / g mg / g pg / g pg / g 62 © 2018 Synlogic, I
Slide 63: Pharmacodynamic Characterization of SYNB1891
© 2018 Synlogic, Inc. All rights reserved. 63 Pharmacodynamic Characterization of SYNB1891 d1 B16-F10 or CT-26 tumors ~100 mm3, randomize groups d4 Harvest Tumor TissueIsolate Tumor Infiltrating LymphocytesPerform RNAseq on Purified T cells Saline or 109 cfu SYNB1891-PT2, i.t. SALINE SYNB1891-PT2 SA