Exhibit 99.1
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
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 this presentation regarding strategy, future operations, future financial position, future revenue, projected expenses, prospects, plans and objectives of management are forward-looking statements. In addition, when or if used in this presentation, the words “may,” “could,” “should,” “anticipate,” “believe,” “estimate,” “expect,” “intend,” “plan,” “predict” and similar expressions and their variants may identify forward-looking statements. Examples of forward-looking statements include, but are not limited to, the approach we are taking to discover and develop novel therapeutics using synthetic biology; statements regarding the potential of our platform to develop therapeutics to address a wide range of diseases including: inborn errors of metabolism, liver disease, inflammatory and immune disorders, and cancer; the future clinical development of Synthetic Biotic medicines; the potential of our technology to treat hyperammonemia and phenylketonuria; the expected timing of our anticipated clinical trial initiations; the benefit of orphan drug and fast track status; the adequacy of our capital to support our future operations and our ability to successfully initiate and complete clinical trials; the results of our collaborations; and the difficulty in predicting the time and cost of development of our product candidates. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: the uncertainties inherent in the preclinical development process; our ability to protect our intellectual property rights; and legislative, regulatory, political and economic developments, as well as those risks identified under the heading “Risk Factors” in our filings with the SEC. The foregoing review of important factors that could cause actual events to differ from expectations should not be construed as exhaustive and should be read in conjunction with statements that are included herein and elsewhere, including the risk factors included in our quarterly Report on Form 10-Q filed with the SEC on August 9, 2018. The forward-looking statements contained in this presentation reflect our current views with respect to future events. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so. These forward-looking statements should not be relied upon as representing our view as of any date subsequent to the date hereof. © 2018 Synlogic, Inc. All rights reserved. 2
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 immune recognition and therapy Dmitriy Zamarin, MD, PhD Memorial Sloan Kettering Cancer Center1:10 pm 1:40 pm Review of SYNB1891 data and program Jose Lora, PhD VP, Research, Synlogic Inc.1:40 pm 2:00 pm Q&A and closing remarks Aoife Brennan © 2018 Synlogic, Inc. All rights reserved. 3 Agenda
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 Programmable PotencyPathways, Combinations, Biomarkers PROGRAMMABLE POTENCY SWITCHES FOR CONTROL, TUNING LOCAL, REDUCED SYSTEMIC TOXICITY
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-Oncology 2 Hyperammonemia -Hepatic Encephalopathy Immuno-Oncology 3 SYNB1020 © 2018 Synlogic, Inc. All rights reserved. Synthetic Biotic Platform Breadth and Potential: Pipeline Focused on Three Therapeutic Areas 5 SYNB1891
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 Recognized as Earliest Immunotherapy Engineer a Living Solution: Synthetic Biotic Medicines Reimagining Early Immunotherapy for Combinatorial Effect Synlogic Immuno-Oncology Approach Rationally Designed for Combinatorial EffectLocally Inflame the TME Systemically Drive Tumor Antigen-Specific Immunity In Situ Vaccination: Neo-antigen Priming and Sustained Immune Response
© 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 checkpoint inhibitors, for example: Colorectal - MSSPancreatic Prostate – castrate resistantBreast – ER+, hormone therapy refractory Enable broad response and remission through engagement of multiple immunomodulatory pathways to enhance tumor inflammation and promote robust T cell responses TREATMENT FAILURES UNRESPONSIVE TUMORS ORR for Select FDA approved CPI Monotherapy 45% 40% 29% 13-14% NSCL 1st line Melanoma 1st line Bladder 1st line Cervical / Gastric 2nd line Non-responders
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
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%Nivolumab: RR ~ 28%Atezolizumab: RR ~ 15%-26% Robert NEJM 2015Wolchok NEJM 2013Garon NEJM 2015Reck NEJM 2016Ferris NEJM 2016Chow J Clin Oncol 2016Bellmunt 2017Rosenberg 2016
Classification by tumor immune phenotype in urothelial cancers Immune excluded (CD8 trichrome stain) Mariathasan S. Nature 2018
Immunotherapy: unmet need MSI-H: ~5% of mCRC Siegel CA J Cancer Clin 2018 Ovarian cancerSoft tissue sarcomasGliomaMyeloma
Predictive factors for response to immune checkpoint inhibitors PD-L1 expression TMB MSI-H/dMMR
Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle Chen DS. Immunity 2013
Mechanisms of immunoresistance Syn Lancet Oncol 2017Blank Science 2016
Converting Cold Tumors into Hot Haanen Cell 2017
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
Anticancer activity of single intratumor injection of Clostridium Novyi-NT Janku CRI-CMIT-EATI-AACR 2018
Cytokine response after single intratumor injection of Clostridium Novyi-NT Janku CRI-CMIT-EATI-AACR 2018
Antitumor Activity of STING Barber Nat Rev Immunol 2015
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 patients): G2 erythema multiforme (1), G3 injection site pain (1), G3 skin/tumor necrosis (1) AEs: Pyrexia (65.2%/42.9%), chills (39.1%/25%), injection site pain (47.8%/10.7%), fatigue (34.8/25%)
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 lesions observed PRs were durable (>6 months)Median 83% reduction in size of target lesions for responders
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 injection site reaction (1 each; 2.4%). On-treatment tumor biopsies showed increases in CD8 T cells infiltrating the injected tumors in a subset of patients. PR: Merkel cell (CPI naïve), Parotid gland (CPI pretreated), both response appear to be durable Meric-Bernstam. SITC 2018
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)
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, prostate cancer, ovarian cancer, MSS colorectal cancer and sarcomas, which creates unmet need for novel therapeutic approachesTurning cold tumors into hot with activators of innate immunity such as STING agonists (and others) offers a new promising approach to increase efficacy of cancer immunotherapy
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
Type I IFN: the first cytokine Alick Isaacs Jean Lindenmann Isaacs, A., and Lindenmann, J., Proc. Roy. Soc., B, 147, 258 (1957)
Functions of type I IFN in infection Ivashkiv et al. Nat Rev Immunol 2013
Cross-talk between type I IFN and adaptive immunity Trinchieri G, JEM 2010.
Type I IFN- related transcripts correlate with T cell infiltration in tumors Fuertes M.B. et al., JEM. 208:2005-16 (2011)
Type I IFN signature is associated with clinical benefit from ipilimumab in melanoma Chiappinelli et al., Cell 2015
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
Mechanisms of activation of type I IFN pathway
STING pathway is required for immune recognition and elimination of tumors. Woo …. Gajewski. Immunity 2015.
Therapeutic strategies to target type I IFN pathway in cancer TLR agonistsSTING agonistsVirusesBacteriaEngineered viruses and bacteria
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
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 trafficking Insufficient priming Monotherapies Often Fail to Overcome Tumor Evasion Mechanisms Recognized Need to Combine Mechanisms to Broaden the Benefit of Immunotherapy Adapted from Chen, Melman; Immunity 2013
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 Survival and Activity Relieve ImmunosuppressionConsume immunosuppressive metabolitesProduce checkpoint inhibitors Rational Design of Key Immunostimulatory Mechanisms in a Bacterial Chassis Synthetic Biotic Medicines Engineered for Efficacy TUMOR LYMPH NODE Systemic Tumor Antigen-Specific Immunity Locally Inflame the TME © 2018 Synlogic, Inc. All rights reserved.
© 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: Enzymatic activity Large Engineering Toolkit: Design to sense / respond to inducerManufacturability: No mammalian cell culture Low Systemic Risk: Initial programs intratumoralNon Pathogenic: Probiotic chassis, antibiotic deactivation
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 Survival/proliferation in tumors 10-15 days post-single dose.Potential for limited injections 30 mins 24 hrs 72 hrs Image of Tissue Reporter Signal Tumor Cross Section Chassis Distribution Behavior within TME in B16.F10 Mice
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 c-di-AMP (CDA)Dual biosafety feature via auxotrophiesLearnings inform future combinations Dual Innate Immune ActivatorSynthetic Biotic Medicine Producing STING Agonist: SYNB1891 © 2018 Synlogic, Inc. All rights reserved. 13
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 Gram-negative BacteriaE.Coli Nissle TLR4 IL-6, p50 p65 NF-κB APC Bacterial Intracellular TLR4 Signaling TLR4 3 Gram-negative BacteriaE.Coli Nissle IFN-b1 Type 1 IFN P IRF3 Phagosome TRIF TRAM Promotes Trafficking, Immune Activation/Proliferation, Priming Bacterial cGAS-STING Activation 2 Gram-negative BacteriaE.Coli Nissle TLR4 IFN-b1 Type 1 IFN P IRF3 2’3’-cGAMP STING cGAS dsDNA(pathogen, host)
SYNB1891 Leverages Natural Phagocytic Activity of Antigen Presenting Cells © 2018 Synlogic, Inc. All rights reserved. 45 CDA Agonizes STING in Natural Context
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
© 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 Soluble Ligand Synthetic Biotic Soluble Ligand CDA(nmol/well) CDA(nmol/well) Naked CDA SYNB1891 STING Knockout Human STING Alleles
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
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 CDA along with Innate Cytokines Prototype Elicits Inflammation-related Gene Signature in Injected Tumors Additional Innate Immune Markers Dose Dependent IFNβ Following 1 Injection
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 © 2018 Synlogic, Inc. All rights reserved. Saline SYNB1891 (1e8 CFU) SYNB1891 (1e9 CFU) Dose Dose Saline SYNB (1e9 CFU) SYNB1891 (1e9 CFU) Dose
© 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) SYNB1891-PT1 (1 x 107) SYNB1891-PT1 (5 x 107) SYNB1891-PT1 (1 x 108) Control Dose-dependent Anti-tumor Activity of SYNB1891 Prototype Strain as a Single Agent
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
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 Tumor Antigen-specific T Cell CD8a © 2018 Synlogic, Inc. All rights reserved. 23
© 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 of STING and Bacterial-Induced Immune Pathways Within APCsDose-dependent Anti-tumor ActivityImmunological MemoryIND Submission 2H19 Dual Innate Immune Activator SYNB1891 A STING Agonist-producing Synthetic Biotic Designed to Locally Inflame the TME and Systemically Drive Tumor Antigen-Specific Immunity
© 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
© 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 Pipeline of Synthetic Biotic Effectors Poised to Deliver Chassis effect5FC5FUSTINGαCD40 scFv/CD40L TNFαIFNγαCD47 ScFv / SirpαGM-CSF TUMOR LYMPH NODE Systemic Tumor Antigen Specific Immunity Locally Inflame the TME
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
© 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 of STING and Bacterial-Induced Immune Pathways Within APCsDose-dependent Anti-tumor ActivityImmunological MemoryIND Submission 2H19 Dual Innate Immune Activator SYNB1891 A STING Agonist-producing Synthetic Biotic Designed to Locally Inflame the TME and Systemically Drive Tumor Antigen-Specific Immunity
© 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
© 2018 Synlogic, Inc. All rights reserved.
© 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:Abx+ SYNB1891 DAP/Thy dln EcN:dacAintegrated:FnR-inducible:Abx-
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, Inc. All rights reserved.
© 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 SALINE SYNB1891-PT2 CT26 B16 cytokine receptor cytokine cytokine Immune response cytokine inflammation inflammation inflammation inflammation inflammation inflammation Immune response cytokine cytokine receptor cytokine cytokine receptor cytokine cytokine Immune response cytokine cytokine Immune response Immune response Immune response inflammation Immune response Prototype Elicits Inflammation-related Gene Signature in Injected Tumors