Seres Therapeutics, Inc. · NASDAQ:MCRB
Seres Therapeutics — Investor Day (May 2018)
99 slides from Seres Therapeutics's investor day presentation, May 24, 2018
Slide 1: Seres Therapeutics 2018 R&D Event
Seres Therapeutics 2018 R&D Event Focus on microbiome impact on immune biology: Ulcerative Colitis and immuno-oncology May 24, 2018 New York City Lea ding the Micro bio me Revo lut io n
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, statements on the timing and results of our clinical trials, the sufficiency of our financial reso
Slide 3: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening Remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 4: Seres leadership biographies
- Roger Pomerantz, M.D. is Seres President, CEO, and Chairman of the Board. Previously, he held a series of senior leadership positions at Merck & Co., Inc. Dr. Pomerantz is an internationally recognized expert in HIV molecular pathogenesis and latency and has developed ten approved infectious disea
Slide 5: Seres Mission: Transform the lives of patients worldwide
Seres Mission: Transform the lives of patients worldwide with revolutionary microbiome therapeutics • First publicly traded company focused on microbiome therapeutics • First clinical study starts: • Biologically sourced microbiome therapy – SER-109 for multiply recurrent C. diff. • Fermented, ratio
Slide 6: R&D capabilities drive drug development productivity
R&D capabilities drive drug development productivity Computational & systems biology (bacterial identification and functional characterization) Vast bacterial strain library Preclinical model systems GMP manufacturing Clinical datasets Seres is the only company with clinical efficacy/ safety data an
Slide 7: Robust microbiome therapeutics pipeline
Robust microbiome therapeutics pipeline PRECLINICAL PHASE 1b PHASE 2 PHASE 3 SER-109 Recurrent C. difficile Pivotal study SER-287 Ulcerative colitis Phase 2B SER-262 Primary C. difficile Immuno-oncology – in combination with anti- SER-401 PD-(L)1 therapy SER-301 Inflammatory Bowel Disease (IBD) Prev
Slide 8: C. difficile infection
C. difficile infection Clinically demonstrated link to GI microbiome dysbiosis Infectious disease caused by toxin-producing anaerobic, spore-forming bacteria, resulting in diarrhea, abdominal pain, fever, and nausea Leading U.S. cause of hospital-acquired infection • Approximately 29,000 deaths/year
Slide 9: Phase 3 SER-109 ECOSPOR III study – enrollment progress ongoing
Phase 3 SER-109 ECOSPOR III study – enrollment progress ongoing • FDA Breakthrough and Orphan Drug designation • Based on FDA feedback, ECOSPOR III designated as a Phase 3 study • Phase 3 study incorporates key learnings from prior clinical studies: • SER-109 dose is approximately 10-fold higher tha
Slide 10: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening Remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 11: The microbiome is essential to human health
The microbiome is essential to human health • Human gastrointestinal microbiome is a vast interacting network of organisms • Microbial ecology provides essential functions for the host: • Modulation of immune system • Colonization resistance against potential pathogens • Regulation of host metabolis
Slide 12: Microbiome PK and PD may be measured
Microbiome PK and PD may be measured, and are increasingly well understood Pharmacokinetics (PK) ● Kinetics of product engraftment: the presence of bacteria in the drug in subjects over time Pharmacodynamics (PD) ● Overall changes in the composition of the microbiome and corresponding alterations in
Slide 13: Modification of the microbiome results in downstream changes in biology
Modification of the microbiome results in downstream changes in biology Illustrative data from various Seres programs Microbiome change Active metabolites Impact on (Pharmacokinetics) (Pharmacodynamics) downstream biology Species Metabolites 13
Slide 14: Multiple factors are now accelerating microbiome drug development
Multiple factors are now accelerating microbiome drug development Company External Environment • Accumulating clinical data (efficacy, • NIH & government agency funding safety, PK/PD) accelerating basic microbiome • Powerful new research tools research • Advanced manufacturing • Increasing large pha
Slide 15: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 16: Ulcerative Colitis (UC)
Ulcerative Colitis (UC) Symptoms Appearance Complications • Abdominal pain • Inflammation • Strictures • Diarrhea • Ulcers • Cancer • Urgency • Megacolon • 80% with at least one relapse within 10 years of diagnosis • 20% require colectomy for acute complications or refractory disease Solberg I et al
Slide 17: Rising incidence of Ulcerative Colitis
Rising incidence of Ulcerative Colitis 20 18 Incidence per 100,000 population (%) per year 16 14 12 10 8 6 4 2 0 1930 1940 1950 1960 1970 1980 1990 2000 2010 Ungaro et al. Lancet. 2016 17
Slide 18: Natural history of Ulcerative Colitis
Natural history of Ulcerative Colitis Solberg I et al. Scand J Gastro 2009; 44:431-440. 18
Slide 19: Classification of Ulcerative Colitis severity
Classification of Ulcerative Colitis severity SEVERE FULMINANT • >6 bloody • >10 stools/day stools/day • Continuous bleeding MODERATE • Fever • Toxicity • ≥4 stools/day • Tachycardia • Abdominal ± blood tenderness/distension • Anemia or • Minimal signs • Transfusion requirement MILD ESR of toxicit
Slide 20: Pathogenesis
Pathogenesis Gut Lumen Microbial communities Environmental Triggers Gut Epithelium Genetic susceptibility Lamina Propria Immune Dysfunction Blood Vessel 20
Slide 21: Microbiome is critical to epithelial integrity
Microbiome is critical to epithelial integrity Microbiota metabolize dietary fiber into short chain fatty acids (SCFAs), critical to gut integrity Belkaid Cell 2014 Sartor Gastro 2008; Sokol IBD 2009; Lopetuso Gut pathogens 2013; Morgan Genome Biol 2012; Backhed 2012; Cell Host Microbe Fig 1A and Fi
Slide 22: Microbiota support mucosal immunity
Microbiota support mucosal immunity Gut homeostasis is maintained through a dialogue between the microbiota and the innate, adaptive, and regulatory immune systems Saleh Immunity 2011, Backhead Cell Host Microbe 2012 Johansson PNAS 2011; Buela KA, Omenetti 2015 DOI: 26398682; Planer JD Peng Science
Slide 23: IBD patients have microbiome dysbiosis
IBD patients have microbiome dysbiosis Imhann et al., Gut 2017 (n=895) Papa et al PLOS One 2012 (n=91) IBD Healthy Enterobacteriaceae Firmicutes • Decreased abundance of short chain fatty acid (SCFA) producing organisms 23
Slide 24: Microbial stimuli can trigger inflammatory cytokine cascade
Microbial stimuli can trigger inflammatory cytokine cascade Microbial products or Mucosal barrier antigens stimulate mucosal immune Antimicrobial effectors cells and activate TLRs to produce Tolerance pro-inflammatory cytokines Tolerance 24
Slide 25: Enterobacteriaceae promotes, and Clostridiales suppresses, inflammation
Enterobacteriaceae promotes, and Clostridiales suppresses, inflammation Winters et al. EMBO Reports 2013 25
Slide 26: Microbiome acts through multiple pathways to alter immunological tone
Microbiome acts through multiple pathways at physiologically relevant concentrations to alter immunological tone • Specific consortia of microbes affect T cell Existing Agents All Act on Same activation, cytokine networks and immune Side of Gut Epithelium cell trafficking Gut Lumen • Demonstrated mo
Slide 27: Microbiome therapeutics represent a novel modality to treat intestinal inflammation
Microbiome therapeutics represent a novel modality to treat intestinal inflammation Potential of Microbiome Therapeutics: 1. Address key components of IBD pathogenesis 2. Offer safety advantages over current agents 3. Ideal for combination therapy 27
Slide 28: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 29: SER-287 overview
SER-287 overview • Consortium of Firmicute bacterial spores • Biologically sourced from healthy screened donors • Spore purification process mitigates risk of transmission of infectious agents SER-287 • Spores are resistant to gastric acid allowing Composition & formulation into capsules Rationale f
Slide 30: Fecal microbiota transplantation has established proof of concept in UC
Fecal microbiota transplantation has established proof of concept for the role of the microbiome in Ulcerative Colitis • McMaster University, Toronto1 ○ 70 patients with active UC; 6x FMT q1 week ○ 24% remission in FMT vs. 5% in POB at 7 weeks ○ Responders increased microbiota diversity ○ 7 responde
Slide 31: SER-287 Phase 1b study objectives
SER-287 Phase 1b study objectives Primary Objectives: • Safety and tolerability • Engraftment of SER-287 dose species into the recipient Select Secondary Objectives Evaluated at Week 8 of induction: • Clinical remission defined as Total Modified Mayo Score (TMMS) ≤2 plus endoscopic subscore (ESS) of
Slide 32: SER-287 Phase 1b Ulcerative Colitis study
SER-287 Phase 1b Ulcerative Colitis study Placebo pre- Placebo once daily for treatment for 6 days 8 weeks (n=11) Vancomycin pre- SER-287 once daily for 58 mild- treatment for 6 days 8 weeks (n=15) moderate UC patients failing standard Placebo pre- SER-287 once weekly of care* treatment for 6 days f
Slide 33: Why pretreat with antibiotics?
Why pretreat with antibiotics? Creates an “ecologic niche” for better engraftment of SER-287 species 33
Slide 34: Why pretreat with antibiotics? Why oral vancomycin?
Why pretreat with antibiotics? Creates an “ecologic niche” for better engraftment of SER-287 species Why oral vancomycin? Rationale: • Favorable safety profile with minimal systemic exposure • Low risk for inducing Clostridium difficile infection • Has activity against Gram positive anaerobes which
Slide 35: Significant and dose dependent impact on remission
Significant and dose dependent impact on remission 40.0% (6/15) 40% achieving remission 30% p = 0.0237 % patients 17.7% 20% (3/17) 13.3% (2/15) 10% 0.0% (0/11) 0% Placebo Vancomycin Placebo Vancomycin pretreatment / pretreatment / pretreatment / pretreatment / Placebo SER-287 daily SER-287 weekly SE
Slide 36: Dose dependent impact on endoscopic improvement
Dose dependent impact on endoscopic improvement 40.0% (6/15) 40% 33.3% endoscopic improvement (5/15) % patients with 30% p = 0.178 23.5% (4/17) 20% 9.1% (1/11) 10% 0% Placebo Vancomycin Placebo Vancomycin pretreatment / pretreatment / pretreatment / pretreatment / Placebo SER-287 daily SER-287 weekl
Slide 37: Illustrative endoscopy improvement — SER-287 daily treatment
Illustrative endoscopy improvement — SER-287 daily treatment Pre-treatment endoscopy showing the Post-treatment day 64 sigmoid colon with spontaneous endoscopy bleeding and ulceration 37
Slide 38: Histological healing
Histological healing RHI score change 8 weeks post SER-287 administration Placebo PBO/SER287 Placebo Vanc/SER287 Vancomycin Vanc/SER287 Vancomycin PBO/PBO / pretreatment weekly / pretreatment Weekly / pretreatment Daily / pretreatment Placebo SER-287 weekly SER-287 weekly SER-287 daily 2 (n=10) (n=1
Slide 39: Analysis of patients previously treated with biologics
Analysis of patients previously treated with biologics • 6 patients in the study were previously treated with biologics for ulcerative colitis: o4 patients in vanco pre-treat, SER-287 daily arm oOne in vanco pre-treat, SER-287 weekly arm oOne in placebo arm • Of the 4 patients in the vanco pre-treat
Slide 40: Favorable SER-287 Phase 1b safety profile
Favorable SER-287 Phase 1b safety profile • SER-287 administration arms demonstrated a similar safety profile to placebo • No serious drug-related adverse events • No subject discontinuations in the SER-287 daily treatment arm • Reduced gastrointestinal adverse events provide an independent assessme
Slide 41: SER-287 Engraftment & Mechanism of Action
SER-287 Engraftment & Mechanism of Action Leading the Microbiome Revolution 41
Slide 42: SER-287 Phase 1b PK and PD results support mechanism of action
SER-287 Phase 1b PK and PD results provide support for the mechanism of action Pharmacokinetics (PK) • Kinetics of product engraftment: the presence of bacteria in the drug in subjects over time Pharmacodynamics (PD) • Overall changes in the composition of the microbiome and corresponding alteration
Slide 43: Pharmacokinetics: Significant engraftment of SER-287 species
Pharmacokinetics: Significant engraftment of SER- 287 species starting 7 days post treatment SER-287 Dosing Period Follow-up * * P < 0.05 * * * * Placebo / Placebo Number SER-287 Species * * 30 * * Placebo / SER-287 Weekly * * * * * * Vanco pre-tx / SER-287 Weekly * * * * Vanco pre-tx / SER-287 Dail
Slide 44: Bacterial species signature associated with clinical remission
Identified bacterial species signature that associates with clinical remission vs non-remission Remission Non-remission Relative species 7 days 10 days 14 days 56 days 84 days 7 days 10 days 14 days 56 days 84 days abundance Less More 19 Species more prevalent in patients achieving clinical remissio
Slide 45: Signature species correlated with metabolite shifts
New Seres data Pharmacodynamics: Signature species associated with clinical remission are strongly correlated with metabolite shifts within SER-287 treated patients Signature Species • Strong correlation between species and metabolites that predict clinical remission Species or Metabolite Outcome As
Slide 46: Metabolic pathways modulated by SER-287 impact inflammatory and immune state
New Seres data Metabolic pathways modulated by SER-287 and associated with clinical remission impact inflammatory and immune state • Short Chain Fatty Acids (SCFAs): o Promote anti-inflammatory responses: enhance epithelial tight junctions, increase in regulatory T cells (Treg), inhibit histone deac
Slide 47: Bile acid metabolism can impact IBD and immune regulation
Bile acid metabolism can impact IBD and immune regulation BSH* Primary Bile Acids 7αDH* Secondary Bile Acids Liver (1° BA) (2° BA) Glycine/Taurine Cholic acid (CA) Deoxycholic acid (DCA) Conjugates Chenodeoxycholic acid (CDCA) Lithocholic acid (LCA) Additional 2° *microbial mediated metabolism Bile
Slide 48: Secondary bile acids metabolism is increased in subjects with clinical remission
New Seres data Secondary bile acids metabolism is increased in subjects with clinical remission Secondary bile acids (2° BA) derived Secondary bile acids (2° BA) have from microbial mediated metabolism are confirmed dose dependent anti- positively associated with clinical inflammatory effects in per
Slide 49: SER-287 Phase 1b data demonstrate clinical effect and mechanistic data
SER-287 Phase 1b data demonstrate clinical effect and provide supportive molecular mechanistic data METABOLITES & CLINCAL OUTCOME SPECIES SIGNATURES PATHWAYS Metabolites and functional Dose dependent Engraftment (PK) associated pathways (PD) associated with clinical remission with clinical remission
Slide 50: SER-287 Presentations at Digestive Disease Week 2018
SER-287 Presentations at Digestive Disease Week 2018 Oral Presentation: SER-287 Phase 1b clinical trial results in mild-to-moderate ulcerative colitis during “Distinguished Abstract Plenary” • Date: June 2nd 10:30-10:45 am • Speaker: Bharat Misra, M.D. (Borland Groover Clinic) Late Breaker Poster: D
Slide 51: Planned SER-287 Phase 2B study design
Planned SER-287 Phase 2B study design • Study to further evaluate induction dosing and longer term maintenance efficacy • Design expected to support potential FDA registrational data package and with compelling data may be considered a pivotal trial • Expect to initiate study in the coming months 26
Slide 52: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 53: Sequential Therapies for Ulcerative Colitis
Sequential Therapies for Ulcerative Colitis Therapy according to severity & prognosis at presentation or failure at prior step Disease Severity at Presentation Anti-TNF +/- What’s New? immunosuppressant Anti-Integrin +/- Anti-TNF/Anti-Integrin Severe immunosuppressant +/- immunosuppressant Aminosali
Slide 54: Success and failure in IBD drug development
Success and failure in IBD drug development Epithelial cell Rituximab Ocrelizumab Rituximab Ustekinumab Ocrelizumab MEDI2070 Dendritic β cell cell Briakinumab IL-12 IL-23 B-7 T cell Activated Success CD-28 macrophage Tofacitinib CD-3 Visilizumab Jak3 Abatacept p38 Th0 T cell JNK IL-12 Fontolizumab I
Slide 55: Less than 30% remission rates in recent clinical studies
Less than 30% remission rates in recent clinical studies Epithelial cell Rituximab Ocrelizumab Ustekinumab MEDI2070 Dendritic β cell cell Briakinumab IL-12 IL-23 B-7 T cell Activated Tofacitinib Success CD-28 macrophage CD-3 Visilizumab Jak3 Abatacept p38 Th0 T cell JNK IL-12 Fontolizumab IFN-γ TGFβ
Slide 56: Drug development has followed a standard path so far…
Drug development has followed a standard path so far… 56
Slide 57: Current indications & consequences for biologics
Current indications & consequences for biologics Indications Consequences • Moderate-Severe Disease • Steroid-Refractory/Steroid- • Not Responding to Conventional Dependent Agents (or Anti-TNF agents) • No benefit & all risks • Long-disease duration • Least likely to respond o Refractory disease o T
Slide 58: Favorable SER-287 efficacy relative to approved and development stage UC drugs
Favorable SER-287 efficacy relative to selected approved and development stage UC drugs Remission Rates for Induction in Active UC FDA approved for UC In development for UC SER-287 40.0% 40.0% 39.0% 34.0% 33.0% 31.6% 28.0% 25.0% 24.0% 21.8% 18.5% 18.5% 17.8% 16.5% 15.0% 17.0% 16.6% 16.0% 13.0% 13.8%
Slide 59: Current management of UC is directed towards host immunosuppression
Current management of UC is directed towards host immunosuppression Focus of drug discovery for past two decades Rationale for targeting immune response: • UC pathogenesis is thought to arise from disruption of immune tolerance to the gut microbiota in a genetically susceptible host • R&D efforts ha
Slide 60: Current management of UC is directed towards host immunosuppression
Current management of UC is directed towards host immunosuppression To date, there are no approved UC drugs targeting the triggers of inflammation rather than inflammation itself Unmet need for an oral nonimmunosuppressive therapeutic agent for UC treatment Sartor Gastro 2017; Sartor Gastro 2008 60
Slide 61: Improved 1st Line Therapies
Improved 1st Line Therapies Disease Severity at Presentation What’s New? Anti-TNF +/-IS Anti-TNF/Anti-Integrin Severe Anti-Integrin +/- IS +/- IS Corticosteroid Aminosalicylate/ Moderate Thiopurine/MTX Aminosalicylate Aminosalicylate Mild Oral/Topical/Combo Oral/Topical/Combo Budesonide Induction Ma
Slide 62: Replacement of Steroids
Replacement of Steroids Disease Severity at Presentation What’s New? Anti-TNF +/-IS Anti-TNF/Anti-Integrin Severe Anti-Integrin +/- IS +/- IS Corticosteroid Aminosalicylate/ Moderate Thiopurine/MTX Aminosalicylate Aminosalicylate Mild Oral/Topical/Combo Oral/Topical/Combo Budesonide Induction Mainte
Slide 63: What Are We Getting?
What Are We Getting? Disease Severity at Presentation What’s New? Anti-TNF +/-IS Anti-TNF/Anti-Integrin Severe Anti-Integrin +/- IS +/- IS Corticosteroid Aminosalicylate/ Moderate Thiopurine/MTX Aminosalicylate Aminosalicylate Mild Oral/Topical/Combo Oral/Topical/Combo Budesonide Induction Maintenan
Slide 64: Potential SER-287 positioning
Potential SER-287 positioning • Potential across broad spectrum of IBD: ✓ Prior to biologics, other therapies with significant safety concerns ✓ Pediatric patients ✓ Following biologics (non-responder patients) ✓ Combination therapy ✓ Other forms of IBD (e.g., Crohn’s disease) 64
Slide 65: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 66: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 67: Robust evidence that microbes play mechanistic role in checkpoint inhibitor response
Robust evidence that microbes play mechanistic role in checkpoint inhibitor response T cell migration DC activation PAMPs Translocation Innate Bacterial Immune migration Stimulation Ag Loaded DC DC Cytokin Bacteria e l Milieu antigens Antigen mimicry Treg -> Th17 T cell maturation Gopalakrishnan Sci
Slide 68: Modulation of inflammation in UC provides rationale for modulating cancer immune set point
New Seres data Modulation of inflammation in UC provides compelling rationale for modulating cancer immune set point Adoptive T cell Transfer Model Key pathways characteristic of human UC Example: Cytokine-Cytokine Receptor are modulated by SER-287 in colitis model Genes shared with human pathway •
Slide 69: MDACC identified microbiome signature in melanoma patients who respond to anti-PD-1
MDACC identified microbiome signature in melanoma patients who respond to anti-PD-1 • Signature driven by bacteria in the class Clostridia, family Ruminococcaceae, including Ruminoccocus and Faecalibacterium • All spore formers that leverage deep Seres expertise in the biology and manufacturing of t
Slide 70: Microbiome signature composition restores anti-PD-1 efficacy after antibiotics
New Seres data Treatment of mice with the microbiome signature composition restores anti-PD-1 efficacy after antibiotics Note: Not all donor-derived bacterial spore compositions result in restoration of anti-PD-1 efficacy 70
Slide 71: Collaborations with leading cancer centers to develop microbiome therapeutics
Collaborations with leading cancer centers to develop microbiome therapeutics Patients treated with PD-1 axis therapies Services: Lung, melanoma, renal, bladder, Hodgkins • Seres option to license foundational • Microbiome samples intellectual property from MD Anderson pre-tx, and at related to the
Slide 72: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 73: Disclosure information
Disclosure information Seres Research and Development Day The gut microbiome and response to cancer therapy Jennifer A. Wargo MD MMSc • I have the following financial relationships to disclose: - Speaker’s bureau: Imedex, Dava, Omniprex, Illumina, BMS - Advisory board member: Roche - Genentech, GSK,
Slide 74: Major advances in cancer treatment through immunotherapy
Major advances in the treatment of cancer through the use of immunotherapy (immune checkpoint blockade) aCTLA-4 aPD-1 aCTLA-4 + aPD-1 However responses are not universal and not always durable, and there is a critical need to identify biomarkers of response, as well as strategies to improve response
Slide 75: How can we better understand responses to therapy and optimize treatment regimens?
How can we better understand responses to therapy and optimize treatment regimens? 75
Slide 76: Responses are dependent on factors shaping tumor growth and immunity
Responses are dependent on factors shaping tumor growth and immunity Systemic Immunity Tumor Genome and Epigenome Innate and Adaptive Tumour cell Tumour cells Epigenetic Changes Tumor Microenvironme Environment nt ECM Internal / External Factors Tumour Stromal cell cell TIL TAF Blood Vessel MDSC Cog
Slide 77: The human microbiome
The human microbiome 100 trillion 10-100X microbes microbial : human genes 3% human body mass largest # microbes – GI tract 1-10X microbes : human cells There is a growing appreciation of the role of the microbiome in health and disease, & evidence that the microbiome can contribute to carcinogenesi
Slide 78: Could the microbiome become the newest frontier in cancer therapy?
Could the microbiome become the newest frontier in cancer therapy, with diagnostic and therapeutic strategies targeting the microbiome? 78
Slide 79: Growing appreciation of the role of the microbiome in cancer
There is a growing appreciation of the role of the microbiome in cancer 79
Slide 80: The microbiome may also influence responses to cancer immunotherapy
The microbiome may also influence responses to cancer immunotherapy Diversity of the gut microbiome is associated Composition of the gut microbiome is with differential outcomes in the setting of associated with differential responses to stem cell transplant in patients with AML checkpoint blockade
Slide 81: Role of the gut microbiome in response to checkpoint blockade in melanoma
Based on this evidence, we wanted to better understand the role of the gut microbiome in response to checkpoint blockade in patients with melanoma 81
Slide 82: Hypothesis
Hypothesis • Differential bacterial “signatures” exist in responders versus non-responders to immune checkpoint blockade • Favorable signatures will be associated with an enhanced anti-tumor immune response (with increased CD8+ T cells, as well as evidence of an enhanced innate immune response) • In
Slide 83: Oral and gut microbiome studied in a large cohort of metastatic melanoma patients
Oral and gut microbiome were studied in a large cohort of patients with metastatic melanoma going onto systemic therapy Responder RECIST at 12 CR, PR, weeks and SD (> 6mos) PFS assessed Initial Tumor Start of Clinical Repeat oral & gut Non- oral & gut biopsy therapy assessment & microbiome Responder
Slide 84: Responders to anti-PD1 had higher gut microbiome diversity
Responders to anti-PD1 had a significantly higher diversity of bacteria in the gut microbiome, and clustered separately from non-responders ** P<0.01 Higher diversity of the gut microbiome was * p<0.05 associated with improved PFS on anti- PD-1 therapy 84
Slide 85: Compositional differences in gut microbiome in responders versus non-responders
Compositional differences in the gut microbiome were also noted in responders versus non-responders to PD-1 blockade Set Responder Low 1 High Responder R NR Set 2 Bacteroidia Set1 Clostridia Clostridia Bacteroidia Set 3 Set2 Non-responder Set3 Non-responder Responders p < 0.05 for LDA>3 or <-3 (FDR
Slide 86: Metagenomic sequencing confirmed taxonomic and metabolomic differences
Metagenomic sequencing confirmed taxonomic differences, and also revealed differences in metabolomic profiles of responders (R) versus non-responders (NR) Enrichment of biosynthetic pathways in R and degradative pathways in NR Gopalakrishnan et al, Science 2018 86
Slide 87: Anti-tumor immune responses compared to gut microbiome composition
Anti-tumor immune responses were assessed and were compared to the composition of the gut microbiome in patients on anti-PD-1 Expression of markers in Bacteroidales abundance Faecalibacterium abundance p<0.05 tumor (IHC) Bacteria enriched in the gut of responders and non-responders High abundance of
Slide 88: Mechanistic studies in murine models link gut microbiome and anti-PD-1 response
Mechanistic studies in murine models demonstrated a link between the gut microbiome and response to anti-PD-1 based therapy Anti-PD-L1 Germ-free mice receiving FMT from responders have delayed tumor growth and enhanced response to anti-PD-L1 Dapi CD45 CD8 Control FMT from NR FMT from R Control FMT f
Slide 89: Can we modulate the gut microbiome to enhance responses to immunotherapy?
Can we modulate the gut microbiome to enhance responses to immunotherapy? 89
Slide 90: Working with Seres and Parker Institute to implement a clinical trial
Working with Seres Therapeutics and Parker Institute for Cancer Immunotherapy to implement a clinical trial to test the hypothesis that modulation of the gut microbiome will enhance responses 90
Slide 91: Gut microbiome signature to help CR donor selection and inform SER-401
Importantly we identified a gut microbiome signature that can help us with CR donor selection, and will inform composition of SER-401 Type 1 Type 2 Importantly, we identified a gut microbiome signature that can help us with CR donor selection and will inform composition of SER-401 Gopalakrishnan et
Slide 92: SER-401 Phase 1b study design
SER-401 Phase 1b study design Study objectives PICI0014 Arm A Fecal microbiota (FM) from All patients = CT scans with complete responders anti PD-1 RECIST week 12 (n=20) Primary endpoint = Arm B safety and tolerability SER-401 (n=20) Secondary endpoints: engraftment, response and Arm C correlative s
Slide 93: Acknowledgements
Acknowledgements Laboratory Investigation (Wargo lab members) Patients and their families •Vancheswaran Gopalakrishnan PhD Seres R&D Day Attendees / Supporters •Christine Spencer PhD Seres Therapeutics •Alexandre Reuben PhD •Roger Pomerantz MD •Miles Cameron Andrews MD PhD •Dave Cook PhD •Luigi Nezi
Slide 94: Agenda
Agenda 8:00-8:10 a.m. 9:05-9:25 a.m. Opening remarks Microbiome therapeutic development Roger Pomerantz, M.D., Seres President, CEO Stephen Hanauer, M.D., Northwestern and Chairman University 8:10-8:20 a.m. 9:25-9:30 a.m. The microbiome as a new therapeutic Break modality Will Dere, M.D., Seres Boar
Slide 95: Appendix
ee Appendix SERES THERAPEUTICS” 95
Slide 96: Demographics
Demographics PBO/SER-287 Vanco/SER-287 Vanco/SER-287 PBO/PBO qWk qWk qD Characteristic (N=11) (N=15) N=17 (N=15) Mean age (years) 45.8 46.5 47.9 47.8 Disease location Left-sided colitis 72.7% 66.7% 70.6% 60.0% Extensive colitis 27.3% 33.3% 29.4% 40.0% Severity of UC Mild 27.3% 40.0% 52.9% 40% Modera
Slide 97: Adverse Events Incidence by Treatment and Organ Class
Adverse Events Incidence by Treatment and Organ Class Pbo/SER-287 Vanco/SER-287 Vanco/SER-287 SER-287 Pbo/PBO Wkly Wkly Daily Overall (N = 11) (N = 15) (N = 17) (N = 15) (N = 47) n (%) n (%) n (%) E n (%) n (%) Gastrointestinal disorders 5 (45.5) 7 (46.7) 8 (47.1) 2 (13.3) 17 (36.2) General disorder
Slide 98: Key inclusion and exclusion criteria
Key inclusion and exclusion criteria Inclusion Criteria Exclusion Criteria • Active mild-to-moderate UC: • Subjects taking cyclosporine • Total Modified Mayo Score (TMMS) 4-10 • Subjects taking biologic therapy • ESS >1, with evidence of mucosal currently or within 3 months prior lesions to randomiz
Slide 99: Engraftment of remission-associated spore-former species
Engraftment of remission-associated spore-former species is greater in subjects with clinical remission across all study arms * P < 0.05 * * * * Number of Spore-Former 10 Signature Species Clinical Remission (R) Non-Remission (NR) 5 0 Day 3 Day 7 Day 10 Day 14 Day 56 Day 84 Days Post Initial SER-287