Slide 1: Ulcerative Colitis Investor Event
Ulcerative Colitis June 21, 2021 Investor Event
Slide 2: Forward Looking Statements
Forward Looking Statements Some of the statements in this presentation constitute “forward looking statements” under the Private Securities Litigation Reform Act of 1995, including, but not limited to, our development plans, the promise and potential impact of any of our microbiome therapeutics, the
Slide 3: Agenda and Speakers
Agenda and Speakers Introductory Clinical burden of SER-287 / SER-301 Microbiome in IBD and Remarks Ulcerative colitis Clinical development SER-287 / SER-301 MoA & pharmacology Eric Shaff Stephen Hanauer, M.D. Lisa von Moltke, M.D. President and Chief Executive Officer, Clifford Joseph Barborka Prof
Slide 4: Key Takeaways for Today's Event
Key Takeaways for Today's Event • Seres is a leader in the development of microbiome therapeutics, leveraging prior clinical success and unique core drug discovery and CMC capabilities • UC is an attractive target for microbiome therapeutics; area of strategic focus • Company advancing both SER-287
Slide 5: Established Proof of Concept – SER-109 Phase 3 Results in Recurrent C. difficile
Established Proof of Concept – SER-109 Phase 3 Results in Recurrent C. difficile Infection PRIMARY EFFICACY ENDPOINT RESULTS SER-109 Placebo RR p-Value Time point (N =89) (N =93) (95%CI) (p1/p2) Approximately 88% n (%) of recurrences n (%) of recurrences sustained clinical Week 8 11 (12.4) 37 (39.8)
Slide 6: Ulcerative Colitis Is an Area of Strategic Focus
Ulcerative Colitis Is an Area of Strategic Focus INFECTIOUS DISEASE Preclinical Phase 1b Phase 2b Phase 3 Collaborators 1 SER-109 Recurrent C. difficile – Open label safety study enrollment ongoing SER-155 Antibiotic resistant bacterial infections, bacteremia, & GvHD (Rationally-designed, cultivated
Slide 7: Differentiated Microbiome Therapeutic Core Capabilities
Differentiated Microbiome Therapeutic Core Capabilities Proprietary drug discovery platform Future microbiome therapeutic candidates In-house GMP manufacturing and quality control Cell banking & inoculum Drug substance Drug product Quality control 7 - Seres Therapeutics © 2021
Slide 8: Ulcerative Colitis: Clinical Overview
Ulcerative Colitis: Clinical Overview Stephen B. Hanauer, MD Clifford Joseph Barborka Professor of Medicine Northwestern University Feinberg School of Medicine
Slide 9: Ulcerative Colitis Discussion Topics
Ulcerative Colitis Discussion Topics − UC disease pathology − Clinical presentation − Epidemiology − Current treatment options − Review of late state development candidates − New therapeutic needs − Potential for combination therapy − Potential clinical use of SER-287 Seres Therapeutics © 2021 9
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Slide 13: UC is a chronic condition of the colon and rectum with remission and flares
UC is a chronic condition of the colon and rectum with periods of remission and flares Typical presentation of UC symptoms: Frequent stools/diarrhea Rectal bleeding Abdominal pain Nocturnal bowel Mucus discharge Urgency movements 5 and 10-year cumulative risk of colectomy 10%–15% 1. Feuerstein JD et
Slide 14: Symptoms directly impact the daily lives of patients with UC
Symptoms directly impact the daily lives of patients with UC In a 2007 online cross-sectional survey designed to collect information on the attitudes and perceptions of patients (N=451) with UC about living with their disease: 84% 60% said that frequent trips to the feel like UC has ruined important
Slide 15: IBD prevalence has been increasing in industrialized countries
IBD prevalence has been increasing in industrialized countries since the 19th century Increasing trend of IBD in industrialized countries1 1.3% of US adults (3 million) diagnosed with IBD in 20152 1. Kaplan GG, Ng SC. Gastroenterology. 2017;152:313-321. 2. CDC. Accessed at https://www.cdc.gov/ibd/da
Slide 16: What causes IBD?
What causes IBD? Normal IBD • Normal resident • Dysbiosis/ microbiota bacterial invasion • Immune • Activated inflammatory tolerance cascades • Mucosal • Mucosal homeostasis ulceration 1. Coskun M et al. Trends Pharmacol Sci. 2017;38(2):127-142. 2. Kaplan GG, Ng SC. Gastroenterology. 2017;152:313- 3
Slide 17: IBD is complex
Intricate universe of immune and nonimmune components involved in IBD Immunopathogenesis IBD is complex Nature Reviews | Gastroenterology & Hepatology de Souza, H. S. P. & Fiocchi, C. (2015) Immunopathogenesis of IBD: current state of the art Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.20
Slide 18: IBD is a summation of events culminating in intestinal inflammation
IBD is a summation of events culminating in intestinal inflammation Genetic polymorphisms Genetic modifications Intestinal inflammation Mucosal Stressors Diet Antibiotics disruption Pathogens (stress, (NSAIDs) smoking) Environmental factors Colonization with intestinal flora (mother / diet) Seres Th
Slide 19: Current management of UC is directed towards host immunosuppression
Current management of UC is directed towards host immunosuppression Rationale for targeting immune response Luminal microbial antigens & adjuvants ⚫ UC pathogenesis is thought to arise from disruption of immune tolerance to the gut microbiota in a genetically susceptible host Genetic IBD Immune susc
Slide 20: Treatment strategy for ulcerative colitis
Treatment strategy for ulcerative colitis The AGA suggests early use of biologic agents with or without immunomodulator therapy, [or tofacitinib], rather than gradual step up after failure of 5-aminosalicylates. (Conditional recommendation, very low quality evidence)1 Surgery Anti-TNF Anti-TNF High
Slide 21: Consensus guide algorithm for management of mild-to-moderate UC
Consensus guide algorithm for the management of mild-to-moderate UC Mild-to-moderate ulcerative colitis “Step Up” Approach ⚫ One drug class is introduced at a time to minimize drug Left-sided or Proctitis toxicities extensive disease ⚫ This type of approach is a reactive therapeutic Oral 5-ASA 2-4.8
Slide 22: UC treatment options studied for more than 60 years
UC treatment options have been studied for more than 60 years, with more advancements since 2005 2005: 2018: First biologic approved JAK inhibitor approved 1955: for moderately-to- for moderately-to - First placebo-controlled severely active UC severely active UC study published for corticosteroid u
Slide 23: 5-ASAs and immunomodulators are options for many patients with UC
5-ASAs and immunomodulators are options for many patients with UC 5-ASAs Immunomodulators Adjunctive therapy to biologics*1,2 Induction and maintenance of remission in Effective in mildly active UC, including proctitis, Maintenance in moderately select patients left-sided colitis, and extensive coli
Slide 24: 5-ASAs and immunomodulators may not be appropriate for some patients
5-ASAs and immunomodulators may not be an appropriate therapy for some patients with UC In a systematic review of randomized, controlled trials (N=8928) through 20121: In an observational, European multinational, multicenter retrospective chart review (N=256, n=150§) published in 20163: 41%–48% rela
Slide 25: 40% of patients with UC reported corticosteroid use for ≥4 months
40% of patients with UC reported corticosteroid use for ≥4 months in a year A multinational 2019 survey of patients with UC (n=765) showed: CORTICOSTEROIDS REPORTED USED TO HELP MANAGE THEIR DISEASE 100 40% of patients* with UC required 80 corticosteroids for ≥4 months per year to help % of Patients
Slide 26: Key safety considerations with IBD therapies
Key safety considerations with IBD therapies Cytopenias Infection Anti-TNF Anti-TNF Corticosteroids Thiopurines Thiopurines Methotrexate Tofacitinib Heart failure Anti-TNF Malignancy Anti-TNF Hepatotoxicity Corticosteroids Anti-TNF Thiopurines Thiopurines Methotrexate Immunogenicity Osteoporosis Ant
Slide 27: Current management of UC is directed towards host immunosuppression
Current management of UC is directed towards host immunosuppression Luminal microbial To date, there are no approved drugs antigens & adjuvants targeting the triggers of inflammation rather than inflammation itself Genetic IBD Immune susceptibility response Unmet need for an oral non- immunosuppress
Slide 28: Key classes of emerging therapies
Key classes of emerging therapies • Etrolizumab (anti-β7) Anti-leukocyte trafficking • Anti-MAdCAM Ab antibodies • Subcutaneous formulation of vedolizumab • Brazikumab • Risankizumab Anti-interleukin 23 antibodies • Mirikizumab • Guselkumab Sphingosine-1 phosphate • Ozanimod (FDA approval May 28, 20
Slide 29: Can the arsenal of the microbiome be harnessed for disease remission?
Can the arsenal of the microbiome be harnessed for disease remission? Firmicutes play a key role in modulating gut homeostasis The critical question is: Can we shift an ecologic community towards a healthier functional A technologic revolution in sequencing state in a chronic inflammatory disease li
Slide 30: Clinical outcomes highlight urgent therapeutic gaps
Clinical outcomes highlight urgent therapeutic gaps Isn’t it time to think outside the box? All approaches to date target specific components of the 1 inflammatory cascade Should we expand our therapeutic armamentarium to target 2 other mediators of disease? Seres Therapeutics © 2021 30
Slide 31: Initial positioning for microbiome therapeutics
Initial positioning for microbiome therapeutics (my viewpoint) • Mild-to-moderate UC for patients with inadequate response to aminosalicylates − Advantages • Large therapeutic gap (~50%) • Simple, straightforward trials with validated endpoints • Allows mechanistic studies • Second trial, straightfo
Slide 32: SER-287 & SER-301 Clinical Overview
SER-287 & SER-301 Clinical Overview Lisa von Moltke, M.D. Chief Medical Officer, Seres Therapeutics
Slide 33: SER-287 is an Investigational Microbiome Drug for the Treatment of UC
SER-287 is an Investigational Microbiome Drug for the Treatment of UC ⚫ Consortium of purified Firmicutes bacterial spores associated with gastrointestinal health ⚫ Biologically sourced from healthy screened donors ⚫ Spore purification process mitigates risk of transmission of infectious agents SER-
Slide 34: SER-287 Phase 1b Study Results Published January 2021
SER-287 Phase 1b Study Results Published January 2021 34 - Seres Therapeutics © 2021
Slide 35: Seres Phase 1b Study Design in Mild-to-Moderate UC
Seres Phase 1b Study Design in Mild-to-Moderate UC Pre-conditioning Induction Treatment (6 days) (8 weeks) Arm A N=11 PBO PBO Primary Objectives • Safety and tolerability • Change in composition of Arm B SER-287 Once-weekly 58 N=15 PBO intestinal microbiome active mild- Patient Population moderate •
Slide 36: Daily Dosing of SER-287 Associated with Increased Clinical Remission
Daily Dosing of SER-287 was Associated with an Increased Rate of Clinical Remission 100% Clinical remission defined as: ⚫ Total modified Mayo Score 80% (TMMS) ≤ 2 plus % patients achieving remission ⚫ Endoscopic subscore (ES) of 0 or 1 with blinded central read 60% P = 0.024 40.0% 40% 20% 17.7% 13.3
Slide 37: SER-287 was Well-tolerated
SER-287 was Well-tolerated PBO/ PBO/ Vanco/ Vanco/ PBO SER-287 SER-287 SER-287 daily (N = 11) weekly weekly (N = 15) n (%) (N = 15) (N = 17) n (%) n (%) n (%) • SER-287 similar to placebo All adverse events (AEs) 7 (63.6) 9 (60.0) 14 (82.4) 8 (53.3) 0 0 0 1 (6.7)* • No drug-related SAEs Serious AEs
Slide 38: Seres Phase 2b ECO-RESET Study Design in Mild-to-Moderate UC
Seres Phase 2b ECO-RESET Study Design in Mild-to-Moderate UC Pre-conditioning Induction Treatment (6 days) (10 weeks, once-daily dosing) Arm A PBO PBO Endpoints • Primary: Clinical remission • Key secondary: Endoscopic improvement 203 • Exploratory: maintenance for remitters; open-label for non- act
Slide 39: ECO-RESET: Designed in Accordance with FDA's UC Guidance
ECO-RESET: Designed in Accordance with FDA’s UC Guidance Document (2016), and Could Serve as 1 of 2 Required Pivotal Induction Studies to Support BLA Paradigm of pivotal UC studies* 3-Component Modified Mayo ECO-RESET endpoint definitions supporting UC drug approvals Score (3CMMS) UC drug Score Rang
Slide 40: ECO-RESET: Expected Learnings and Defining Successful Outcomes
ECO-RESET: Expected Learnings and Defining Successful Outcomes Clinical remission (primary endpoint) Clear signal of clinical efficacy versus placebo (mid-2021) Endoscopic remission/improvement, symptomatic remission Clear signal of clinical efficacy versus placebo, supporting the primary endpoint (
Slide 41: SER-301 Design Leveraged Reverse-Translational Experience with SER-287
SER-301 Design Leveraged Reverse-Translational Clinical & Scientific Experience with SER-287 in Mild-to-Moderate UC Preclinical Phase 1b Phase 2b Phase 3 Collaborators INFLAMMATORY SER-287 Mild-to-moderate ulcerative colitis * Mild-to-moderate ulcerative colitis SER-301 (Rationally-designed, cultiva
Slide 42: SER-301-001 Phase 1b Study in Mild-to-Moderate Ulcerative Colitis
SER-301-001 Phase 1b Study in Patients with Active Mild-to-Moderate Ulcerative Colitis: Australia & New Zealand (Currently Enrolling) Cohort 1 Pre-conditioning Induction Treatment Open Label (6 days) (10 weeks, once-daily dosing) 15 patients VANCO SER-301 Endpoints • Primary: Safety & tolerability •
Slide 43: Potential for Further SER-287 Clinical Development in IBD
Potential for Further SER-287 Clinical Development in IBD Clinical development opportunity Details Initiate SER-287 2nd pivotal induction study + pivotal maintenance Progress towards BLA study (single study) • Moderate-to-severe UC • Maintenance treatment after clinical remission with any 1st or 2nd
Slide 44: Seres UC Franchise Summary
Seres UC Franchise Summary SER-287 Phase 2b ECO- RESET study aims to build SER-301 Phase 1b study upon the strong data from aims to investigate safety the Phase 1b study. & tolerability and explore Topline induction data is clinical efficacy signals. expected in mid-2021. Both studies will have tran
Slide 45: Microbe-Host Interactions in IBD & UC
Microbe-Host Interactions in IBD & UC Matthew Henn, Ph.D. Chief Scientific Officer, Seres Therapeutics
Slide 46: Seres' differentiated, innovative platforms enable rapid progress
Seres’ differentiated, innovative platforms enable rapid progress from target ID through clinical development in areas of significant unmet medical need • Integrity of the gastrointestinal microbiome is compromised • Bacteria & microbe-associated metabolites modulate host immune pathways • Addressin
Slide 47: Gastrointestinal Microbiome Involved in Pathogenesis of IBD
Gastrointestinal Microbiome Involved in Pathogenesis of IBD 1275 pubs in 2020 Science Trans. Med. 2018 Cell Host & Microbe Indexed PubMed papers with terms microbiome & 2018 IBD/UC/Crohn’s Nature 2019 Cell 2019 47 - Seres Therapeutics © 2021
Slide 48: Composition of Microbiome Linked to IBD in Adults and Pediatrics
Composition of Microbiome Linked to IBD in Both Adults and Pediatrics Adults with UC, colonic or ileal Crohn’s Pediatric (4-17 yo) with UC Imhann et al. 2018. Gut Schirmer et al. 2018. Cell Host & Microbe 48 - Seres Therapeutics © 2021
Slide 49: Microbe-Associated Metabolites and Antigens Impact Gut Epithelial Integrity
Microbe-Associated Metabolites and Antigens Can Impact Gut Epithelial Integrity and Host Inflammation & Immunity Inflammatory Inflammation Homeostasis Microbial products or Microbe-associated antigens stimulate mucosal metabolites promote immune cells and activate mucosal and epithelial toll-like re
Slide 50: Gastrointestinal Microbiome Intimately Connected to Host Immune System
Gastrointestinal Microbiome Intimately Connected to Host Immune System Function Seres internal data and/or published literature support role of microbes, microbe-associated metabolites, or microbial products and antigens Image adapted from: de Souza, & Fiocchi. 2015. Nat. Rev. Gastro. Hepatol. 50 -
Slide 51: Microbiome Therapeutics for UC
Microbiome Therapeutics for UC
Slide 52: Seres Microbiome Therapeutics are Bacterial Consortia
Seres Microbiome Therapeutics are Bacterial Consortia Designed to Have Specific Pharmacological Properties Designed to target inflammatory & immune pathways & establish colonization resistance to pathogens Figure adapted from Henn et al. 2021. Gastroenterology 52 - Seres Therapeutics © 2021
Slide 53: Seres UC Candidates Target Multiple Triggers of UC Pathology
Seres UC Therapeutic Candidates are Consortia of Bacteria that Have Potential to Target Multiple Triggers of Ulcerative Colitis Pathology SER-287 Drug Bacteria Pro-inflammatory Bacteria • Consortia of Firmicutes Reduce the abundance of bacteria formulated as spores pro-inflammatory bacteria and • Bi
Slide 54: Seres Differentiated Research Engine Delivers End-to-End Drug Development
Seres Differentiated Research Engine Delivers End-to-End Drug Development from Target Identification Through GMP Manufacturing Lead Candidate GMP Manufacturing & Disease Target Identification Hit-to-Lead Identification Optimization Quality Systems Biorepository Strain library In vivo modeling Biolog
Slide 55: SER-287 SER-301 MoA & Pharmacology
SER-287 SER-301 MoA & Pharmacology
Slide 56: SER-287 Phase 1b Study Results Published January 2021
SER-287 Phase 1b Study Results Published January 2021 56 - Seres Therapeutics © 2021
Slide 57: PK: SER-287 Bacteria Durably Engraft and Associate with Remission
PK: SER-287 Bacteria Durably Engraft in Subjects and are Associated with Clinical Remission Preconditioning of microbiome followed by daily dosing of SER-287 was associated with greatest engraftment & clinical remission Num. of engrafting drug species Days Post-Treatment Henn et al. 2021. Gastroente
Slide 58: PD: SER-287 Restructures Microbiome and Reduces Enterobacteriaceae
PD: SER-287 Restructures the Microbiome and Reduces the Abundance of Pro-Inflammatory Enterobacteriaceae SER-287 treatment results in a broad shift in the Decrease in pro-inflammatory overall composition of spore & non-spore gut Enterobacteriaceae species by 8 weeks post-treatment post-treatment is
Slide 59: PD: Clinical Remission Associated with Microbiome and Metabolism Changes
PD: Clinical Remission is Significantly Associated with Changes in Microbiome and Microbe-Associated Metabolism Microbially-mediated metabolites that modulate host inflammation & barrier integrity are significantly associated with SER-287 treatment & clinical remission indole taurine arachidonate lo
Slide 60: PD: Intestinal Biopsy Gene Expression Data Support SER-287
PD: Intestinal Biopsy Gene Expression Data Support SER-287 Treatment Association with Modulation of Multiple Host Inflammation & Immune Pathways Pathways Pathways associated associated 42 101 32 with clinical with treatment remission in with SER-287 UC patients e.g. Shared Pathways Cytokine-cytokine
Slide 61: In vitro Human Cell-Based Assays Confirm SER-287 MoA
In vitro Human Cell-Based Assays Can Confirm SER-287 MoA and Demonstrate Direct Modulation by Drug Bacteria Example: Induce Remission-Associated Transcriptional Changes in Colonic Organoids In Vitro Primary colonic organoids SER-287 Ph1B HumanOrganoids Human Colonic colonic organoids Biopsies SER-28
Slide 62: SER-301: Next Generation Investigational Microbiome Therapeutic for UC
SER-301: Next Generation Investigational Microbiome Therapeutic for UC Designed to Optimize Desired Pharmacological Properties SER-287 microbiome signatures of clinical remission In silico Computational design of consortia In vitro In vivo Microbiome signatures from across In vitro Screening Screeni
Slide 63: In vitro Assays Confirm SER-287 MoA and Optimize SER-301
In vitro Human Cell-Based Assays Can Confirm SER-287 MoA & Enable Optimization of Pharmacological Properties of SER-301 Example: protect epithelial barrier from INFγ-mediated damage in vitro Barrier Permeability SER-287 SER-301 2500 Basal fluorescence 2000 1500 1000 500 0 y y l l ro ro FN N nt nt IF
Slide 64: In vitro Assays Enable Optimization of Consortia Like SER-301
In vitro Human Cell-Based Assays Enable Optimization of Pharmacological Properties of Consortia Like SER-301 Example: Indole production and activation of UC-relevant anti-inflammatory genes in organoid model for UC Concentration (μm) Indole Measured function: indole production • Bacterial tryptophan
Slide 65: SER-301 Promotes Regulatory Immune Responses in Colitis Mouse Model
SER-301 Promotes Regulatory Immune Responses and Does Not Induce Colitis in a Spontaneous Colitis Mouse Model Fecal lipocalin levels remain Anti-inflammatory Pro-inflammatory Th1 and or below baseline Tregs are increased Th17 cells are not induced Microbiome introduced 5-8 week colonization GF Il10-
Slide 66: 'Avatar Mouse' Interventional Treatment Model Using SER-301
‘Avatar Mouse’ Interventional Treatment Model Using SER-301 Attenuates Intestinal Inflammation in the IL10-/- Spontaneous Colitis Mouse Model Rising fecal lipocalin levels reversed back to baseline INFL+ Sustained microbiome lipocalin introduced increase Interventional Treatment INFL+ (SER-301) 3x/w
Slide 67: Opportunity for Microbiome Therapeutics in Additional Therapeutic Areas
Opportunity for Microbiome Therapeutics in Additional Therapeutic Areas Highly productive R&D engine pursuing multiple promising potential opportunities Infectious (e.g. Antibiotic-resistant infections) Inflammatory (e.g. Crohn’s, pouchitis, RA) • Deep understanding of the sweeping role of the micro
Slide 68: Q&A
Q&A