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NYSE MKT: SYN Microbiome Analyst & Investor Meeting New York City June 3, 2015 Forward-Looking Statements This presentation includes forward-looking statements on Synthetic Biologics current expectations
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NYSE MKT: SYN Microbiome Analyst & Investor Meeting New York City June 3, 2015 Forward-Looking Statements This presentation includes forward-looking statements on Synthetic Biologics current expectations and projections about future events. In some cases forward-looking statements can be identified by terminology such as may, should, potential, continue, expects, anticipates, intends, plans, believes, estimates, indicates, and similar expressions. These statements are based upon current beliefs, expectations and assumptions and are subject to a number of risks and uncertainties, many of which are difficult to predict and include statements regarding our clinical trials, our establishment of collaborations and our execution of our growth strategy. The forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those set forth or implied by any forward-looking statements. Important factors that could cause actual results to differ materially from those reflected in Synthetic Biologics forward-looking statements include, among others, a failure of our product candidates to be demonstrably safe and effective, a failure to initiate clinical trials and if initiated, a failure to achieve the desired results, a failure to obtain regulatory approval for our product candidates or to comply with ongoing regulatory requirements, regulatory limitations relating to our ability to promote or commercialize our product candidates for the specific indications, a lack of acceptance of our product candidates in the marketplace, a failure of us to become or remain profitable, a failure to establish collaborations, our inability to obtain or maintain the capital or grants necessary to fund our research and development activities, a loss of any of our key scientists or management personnel, and other factors described in Synthetic Biologics annual report on Form 10-K for the year ended December 31, 2014, subsequent quarterly reports on Form 10-Qs and any other filings we make with the SEC. The information in this presentation is provided only as of the date presented, and Synthetic Biologics undertakes no obligation to update any forward-looking statements contained in this presentation on account of new information, future events, or otherwise, except as required by law. 2 Microbiome Analyst & Investor Meeting Agenda Jeff Riley Microbiome overview Joe Sliman Introductions Mark Pimentel, MD, FRCP(C) Irritable bowel syndrome with constipation (IBS-C) IBS-C Q&A Session Prof. Mark H. Wilcox, MD, FRCPath C. difficile C. difficile Q&A Session 3 Management Team Jeffrey Riley, CEO Pfizer, Nichols Institute (Quest), SmithKline Beecham, QIC Steven Shallcross, CFO Vanda Pharmaceuticals, Inc., Empire Petroleum Partners, LLC, Innocoll AG (formerly privately held Innocoll Holdings, Inc.) John Monahan, Ph.D., EVP R&D Avigen, Somatix, Triton Biosciences, Hoffman-LaRoche Joseph Sliman, M.D., MPH, SVP Clinical/Regulatory Vanda Pharmaceuticals, Inc., MedImmune, Inc., DynPort Vaccine Klaus Gottlieb, M.D., FACG, VP Clinical/Regulatory * Quintiles, U.S. Food & Drug Administration Maureen Early, M.B.A., VP Commercial Rhone Poulenc Rorer/Aventis, Upside Endeavors Amy Sloan, R.A.C., VP Regulatory MedImmune, Inc., DynPort Vaccine * Effective June 22, Investment Proposition NYSE MKT: SYN Microbiome-focused, clinical-stage therapeutics to protect the microbiome while targeting pathogen-specific diseases Addressing multi-billion dollar market opportunities addressing significant unmet medical needs Multiple near-term and long-term clinical milestones Experienced management team with extensive clinical and commercial track record 5 Microbiome Product Pipeline Therapeutic Area Product Candidate Biologic Agent/ Drug Compound Discovery Preclinical Phase 1 Phase 2 Phase 3 C. difficile infection/ Antibioticassociated diarrhea (AAD) SYN-004 Oral enzyme Irritable bowel syndrome with constipation (IBS-C) SYN-010 C Oral drug C - Cedars-Sinai Medical Center collaboration Completed Planned Key Microbiome Achievements Nov 2014 C. difficile Initiated Phase 1a and 1b clinical trials Dec 2014 C. difficile First SYN-004 U.S. composition of matter patent; adds to extensive C. difficile patent estate Dec 2014 C. difficile Positive topline results from Phase 1a clinical trial C. difficile Positive topline results from Phase 1b clinical trial Feb Feb 2015 IBS-C SYN-010 modified-release formulation of Lovastatin C. difficile Positive PK data from Phase 1a and 1b clinical trials Mar 2015 Mar 2015 C. difficile Initiated Phase 2a clinical trial Upcoming Microbiome Milestones 2Q 2015 IBS-C Submit IND to support clinical trials C. difficile Report topline data from Phase 2a clinical trial 2Q Q 2015 IBS-C Initiate Phase 2 clinical trials C. difficile Initiate Phase 2b clinical trial 3Q H 2015 IBS-C Report topline data from Phase 2 clinical trial C. difficile Report topline data from Phase 2b clinical trial 2H IBS-C & C. difficile Initiate Pivotal Phase 3 clinical trials 8 Human Microbiome The Body Has 10 Times as Many Microbe Cells as Human Cells Human Microbiome 1,000,000 Genes Human Genome 23,000 Genes 99% of your DNA Genes are in Microbe Cells (e.g., Bacteria) NOT Human Cells Leveraging the Microbiome Will Radically Change Medicine Source: 9 Diseases Directly Influenced by the Gut Microbiome Source: Genome Medicine 2011, 3:14 10 Human Microbiome Over Time Response to Environmental Conditions and Life Stages Source: US National Library of Medicine. Image source: Ottman N, et al. (2012) The function of our microbiota: who is out there and what do they do? Front. Cell. Inf. Microbio. 2: Joe Sliman, M.D., MPH Senior Vice President, Clinical & Regulatory Affairs Senior Medical Director and Head of Patient Safety and Pharmacovigilance at Vanda Pharmaceuticals Inc. Responsible for a New Drug Application for HETLIOZ (tasimelteon), which is indicated for the treatment of Non-24 Hour Disorder in totally blind adults Medical Director in Vaccines and Infectious Diseases at MedImmune, Inc. Associate Medical Director at Dynport Vaccine Company United States Navy Led the U. S. Pacific Fleet disease surveillance programs, including influenza surveillance, preparedness, and prevention, as well as communicable disease and injury surveillance and prevention and health policy development 12 Klaus Gottlieb, M.D., FACG New Clinical & Regulatory Team Member Quintiles USFDA Gastroenterology Therapeutic Area Lead Senior Clinical Reviewer, Division of Gastroenterology & Inborn Errors As Vice President, Clinical & Regulatory Affairs, Dr. Gottlieb s responsibilities include: Lead the Clinical Study teams through End-of-Phase 2 Assist in development of strategy and execution of Phase 3 13 Irritable Bowel Syndrome with Constipation (IBS-C) Mark Pimentel, M.D., FRCP(C) Microbiome Analyst & Investor Meeting New York City Mark Pimentel, M.D., FRCP(C) IBS-C Keynote Speaker Cedars-Sinai Medical Center Director, GI Motility Program Professor of Medicine Serves as a principal investigator or co-investigator for numerous basic science, translational and clinical studies in IBS, and the relationship between gut flora composition and human Chairman of Synthetic Biologics IBS-C Clinical Advisory Board 15 Novel Treatment of C-IBS based on Microbiome Synthetic Biologics Mark Pimentel, MD, FRCP(C) Professor of Medicine Director, GI Motility Program Up to 15% of the world population has IBS That is equivalent to 1.05 Billion people 50% of visits to a gastroenterologist Hard or Lumpy Stools, % IBS Subtypes Based on Stool Form Type 1* Type 2* IBS-C IBS-M IBS-U IBS-D Type 6* Loose or Watery Stools, % *Bristol Stool Form Scale. IBS-C=constipation-predominant IBS; IBS-D=diarrhea-predominant IBS; IBS-M=mixed IBS; IBS-U=unsubtyped IBS. Longstreth GF, et al. Gastroenterology. 2006;130: Drug Therapy Diarrhea Constipation Abdominal pain/ discomfort Bloating Loperamide Diphenoxylate Alosetron Cholestyramine Antibiotics Fiber Osmotic and stimulant laxatives Lubiprostone Antispasmodics Antidepressants Alosetron Antibiotics Probiotics Camilleri M. Gastroenterology. 2001;120: Drossman DA, et al. Gastroenterology. 2002;123: ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. D-IBS M-IBS C-IBS Non-Constipation-IBS Tricyclic Antidepressants and IBS Antidepressant Action Visceral Analgesia Changes in Motility Smooth Muscle Relaxation (TCA) TCA=tricyclic antidepressants. Adapted from Rome Foundation Functional GI Disorders Specialty Modules. Percent Global Improvement Rifaximin: First Controlled Trial Placebo Rifaximin Weeks after Rifaximin *P=0.02 Mixed Longitudinal Model for 10-week difference Pimentel, et al, Ann Intern Med, 2006 Primary Outcome (4 weeks after Tx) Primary Efficacy Outcome SGA-IBS Weekly Study TARGET 1 TARGET 2 Combined Odds Ratio (95% CI) p-value (1.10,2.12) (1.05,2.01) (1.18,1.88) Key Secondary IBS Bloating Weekly TARGET 1 TARGET 2 Combined (1.16,2.27) (1.08,2.06) (1.23,1.96) Other Secondary SGA-IBS Daily IBS Bloating Daily IBS Ab Pain Daily TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined (1.26,2.47) (1.13,2.24) (1.28,2.04) (1.01,1.97) (1.26,2.44) (1.21,1.92) (1.05,2.02) (1.05,2.03) (1.13,1.78) FDA Proposed Ab Pain & Stool Daily (FDA) Ab Pain Daily (FDA) Stool Consist. Daily (FDA) TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined (1.02,1.92) (1.12,2.13) (1.17,1.84) (1.08,2.03) (1.06,2.00) (1.17,1.83) (1.25,2.59) (1.12,2.21) (1.31,2.14) Pimentel, et al NEJM, Odds Ratio and 95% CI Favors Placebo Favors Rifaximin Durability of Response (3 months) Primary Efficacy Outcome SGA-IBS Weekly Study TARGET 1 TARGET 2 Combined Odds Ratio (95% CI) (1.00, 1.82) (1.13, 2.03) (1.17, 1.77) p-value Key Secondary IBS Bloating Weekly TARGET 1 TARGET 2 Combined (0.95, 1.73) (1.16, 2.09) (1.15, 1.75) Other Secondary SGA-IBS Daily IBS Bloating Daily IBS Ab Pain Daily TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined (1.18, 2.18) (1.09, 1.99) (1.20, 1.83) (1.10, 2.04) (1.24, 2.25) (1.24, 1.89) (1.00, 1.83) (1.01, 1.81) (1.06, 1.61) FDA Proposed Ab Pain & Stool Daily (FDA) Ab Pain Daily (FDA) Stool Consist. Daily (FDA) TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined TARGET 1 TARGET 2 Combined (1.01, 1.83) (1.08, 1.92) (1.14, 1.72) (0.98, 1.75) (1.03, 1.83) (1.09, 1.64) (1.24, 2.33) (1.09, 2.00) (1.27, 1.97) Pimentel, et al NEJM, Odds Ratio and 95% CI Favors Placebo Favors Rifaximin D-IBS M-IBS C-IBS Constipation-IBS SSRI Meta-analysis Study (Year, Drug, Dose) Treatment n/n Control n/n Kuiken (2003, fluoxetine 20 qd) 9/19 12/21 RR (Random) 95% CI Tabas (2004, paroxetine qd) 25/44 36/46 Vahedi (2005, fluoxetine 20 qd) 6/22 19/22 Tack (2006, citalopram qd) 5/11 11/12 Talley (2008, citalopram 40 qd) 5/17 5/16 Subtotal (95% CI) Favors Treatment Favors Control *Significant heterogeneity among studies may limit conclusions. Study duration ranged from 6 weeks to 12 weeks. Ford AC, et al. Gut. 2009;58: RR=0.62 (95% CI= ) NNT=3.5 26 Overall Responders (%) Lubiprostone for IBS-C: Data From Two Phase 3 Trials week treatment period 25 *P= Overall responder: Monthly responder for at least 2 of 3 months Monthly responder: At least moderate relief for 4/4 weeks or significant relief for 2/4 weeks 0 Lubiprostone 8 µg BID Placebo N=780 N=387 Drossman DA et al. Aliment Pharmacol Ther. 2009;29: Lubiprostone: Adverse Effects Placebo N=387 Lubiprostone 8 mcg twice daily N=779 Serious Adverse Events 1% 1% Treatment-related Adeverse Events 21% 22% Nausea 4% 8% Diarrhea 4% 6% Abdominal Pain 5% 4% Cardiovascular-related events (Mild tachycardia reported in 1 patient) 0% 1% Discontinuation due to adverse events 6% 5% Drossman DA et al. Aliment Pharmacol Ther. 2009;29: % Responders Linaclotide Phase 3 Studies in IBS-C: EMA Analysis /12 weeks considerable or complete relief of IBS symptoms 12-Week responder Δ = 15.6% 12-Week responder Δ = 21.1% 12-Week responder Δ = 19.1% * 36.7 * 33.2 * N=395 N=405 N=403 N=401 N=403 N=401 Trial 31 Trial 302 *P .0001 Quigley EMM et al. Aliment Pharmacol Ther 2013;37:49. Linaclotide in IBS-C Phase 3 Trial: Safety Weeks 1 12 Weeks 1 26 Placebo n=403 Lin 290 mcg n=402 Placebo n=403 Lin 290 mcg n=402 Any TEAE 187 (46%) 212 (53%) 228 (57%) 263 (65%) Diarrhea 7 (2%) 71 (18%) 10 (2%) 79 (20%) Nausea 17 (4%) 17 (4%) 24 (6%) 23 (6%) URI 13 (3%) 14 (3%) 22 (5%) 22 (5%) Abdominal pain 14 (3%) 15 (4%) 16 (4%) 18 (4%) Flatulence 7 (2%) 13 (3%) 9 (2%) 15 (4%) Gastroenteritis viral 4 (1%) 8 (2%) 9 (2%) 15 (4%) Headache 8 (2%) 13 (3%) 11 (3%) 13 (3%) TEAE=treatment-emergent adverse event Chey WD et al. Am J Gastroenterol 2012;107:1702 Disadvantages of Current C-IBS therapies Built on the concept of laxative/accelerants Side effects are often diarrhea No biomarker to predict side effects/response Not based on a mechanism known to be important in the pathophysiology of IBS Functional Net Value Diarrhea IBS Shah, et al. Aliment Pharm Ther 2014 Functional Net Value Constipation IBS Shah, et al. Aliment Pharm Ther 2014 IBS and Microbiome 2000 American J Gastroenterol 2000 Dec;95(12): Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Number of Cells 100x more Bacterial cells Bacterial Cells Human Cells Kingdoms of Life Eukaryotes Bacteria Archaea Example: Plants and animals Example: Salmonella, E. coli Example: Methanogens SIBO- What is it? Duodenum Small Bowel ~ 0 cfu/ml Colon cfu/ml Cecum Jejunum Ileum 10 1 cfu/ml 10 2 cfu/ml 10 3 cfu/ml Different Approaches to SIBO Type of Test Breath testing Specific Test Lactulose Breath Test 13C Xylose Breath Test Glucose Breath Test Sucrose Breath Test Sorbitol Breath Test Culture Empiric Approach Small bowel aspirate and culture Test, treat and re-evaluate D-IBS M-IBS C-IBS Non-Constipation-IBS Breath Testing is abnormal in IBS Forest plot of all age-sex matched studies Type of % % Author Breath Test OR (95% CI) CI) Weight Weight Grover sucrose 2.29 (0.89, 5.87) 5.87) Lupascu Pimentel glucose lactulose (3.52, 33.71) 33.71) (5.29, 80.69) 80.69) Parodi glucose 4.30 (1.24, 14.98) 14.98) Scarpellini Collin lactulose lactulose (7.35, 80.15) 80.15) (6.55, 49.71) 49.71) Overall (I-squared = 67.9%, p = 0.008) 9.64 (4.26, 21.82) 21.82) NOTE: Weights are from random effects analysis Shah, et al Dig Dis Sci, 2010 Percent of Subjects Small Bowel Culture in IBS P 0.05 P % 24% Control 12% IBS 4% 10,000 coliforms 5,000 coliforms N=165 IBS, 26 controls Posserud, et al, Gut, 2007;56:802-8. Percent of Subjects SIBO and IBS % P= % Non- D-IBS D-IBS 10 0 N=77 non-d-ibs, N=35 D-IBS Pyleris, et al. DDS, 2012 Agilent Plots of Normal and IBS IBS Healthy Control Pyleris, et al. DDW, 2014 Sequencing Results- Normal small bowel Normal Subjects Pyleris, et al. DDW, 2014 Sequencing Results- IBS small bowel IBS Subjects Pyleris, et al. DDW, 2014 D-IBS M-IBS C-IBS Constipation-IBS Parts Per Million Parts Per Million Parts Per Million Complexities of Gas Production Methane Hydrogen 70 H Hydrogen Producers 20 Methane 10 Producers 0 4H 2 1CH Time (Minutes) H Time (Minutes) H 2 S Producers 5H 2 1H 2 S Time (Minutes) % of patients Methane in C-IBS X 2 =16.6, p 0.001 Constipation Diarrhea H2 CH4 and H2 CH4 Pimentel, et al. Dig Dis Sci, 2003. % Marker Recovery Methane Slows Intestinal Transit n=5, p Room Air 69% mean slowing of transit with CH 4 Methane Pimentel, et al. Am J Physiol, 2006. Methane- Important in C-IBS Meta-analysis of studies % % Author Year OR (95% (95% CI) CI) Weight Weight Peled (0.20, (0.20, 3.56) 3.56) Fiedorek (1.60, (1.60, 11.68) 11.68) Pimentel (2.22, (2.22, 14.03) 14.03) Pimentel (2.48, (2.48, ) ) Majewski (0.70, (0.70, 4.67) 4.67) Bratten (1.14, (1.14, 4.33) 4.33) Parodi (0.79, (0.79, 4.51) 4.51) Hwang (8.73, (8.73, ) ) Attaluri (2.06, (2.06, 6.66) 6.66) Overall (I-squared = 64.6%, p = 0.004) 3.51 (2.00, (2.00, 6.16) 6.16) NOTE: Weights are from random effects analysis Kunkel, et al. Dig Dis Sci, 2011. Methanobrevibacter smithii -M. smithii is the predominant human methanogen -There are no drug development plans around the organism -This organism is important in health and disease Methane Factor Analysis Constipation lack of milk intolerance lack of weight loss small bowel movements straining VAS score After treatment constipation level by group P= Neo+plac Neo+rifax Pimentel, et al. Dig Dis Sci, 2014. VAS score After treatment bloating level by group Neo+plac P 0.01 Neo+rifax Pimentel, et al. Dig Dis Sci, 2013. VAS Constipation Severity Weekly Constipation VAS *P=0.01 P 0.01 +P= Neo+plac 30 + Neo+rifax 20 * 10 0 Pre Tx Post Tx Pimentel, et al. ACG, 2013. VAS Bloating Severity Weekly Bloating VAS *P 0.05 P=NS * Neo+plac Neo+rifax 20 * * 10 0 Pre Tx Post Tx Pimentel, et al. Dig Dis Sci, 2014. VAS Abdominal Pain Severity Weekly Abdominal Pain VAS Neo+plac Neo+rifax Pre Tx Post Tx Pimentel, et al. ACG, 2013. VAS score Final visit constipation severity based on methane 3ppm Analysis of the Neomycin + Rifaximin Group P= Methane 3ppm Methane 3ppm Pimentel, et al. Dig Dis Sci, 2014. Environmental Genetics Cultural GI MICROBES OBESITY DIABETES Psychological Social Meds Psychiatric Methanogen Model- Syntropic Effect Methanobrevibacter smithii Indigestible Substrate Indigestible Substrate H 2 Intoxicates self H 2 H 2 H 2 H 2 CH 4 Energy Digestible Substrates for Host Energy Digestible Substrates for Host = Syntroph = Methanogen % Marker Recovery Methane Slows Transit n=5, p Room Air 69% mean slowing of transit with CH 4 Methane Pimentel, et al. Am J Physiol, 2006. Methane in Obese Patients N=58 No Methane on Breath (n=46) Positive Methane on breath (n=12) P-value Age (yrs) Height (in) Weight (lbs) BMI P= All Subjects No Methane Positive Methane Mathur et al, Gastro and Hep, 2012 BMI Methane in Non-obese Patients Multivariate analysis controlling for age, sex, diabetes, anti depressant and other confounding (P 0.001) Normal Breath test Positive Hydrogen Breath Test N=792 Methane Only Methane and Hydrogen Positive Mathur et al. JCEM 98:E , 2013 Examine the metabolic parameters before and after antibiotic treatment in obese pre-diabetic subjects with methane positive breath tests. To determine whether using an antibiotic to eradicate M. smithii (as measured by breath methane) results in improvement in metabolic profile 11 pre-diabetic (9F, 2M), obese ( kg/m 2 ) methane positive subjects aged years (funded by the ADA) Mathur R et al, ADA 2014 Mathur R et al, ADA 2014 Mathur R et al, ADA 2014 Insulin Sensitivity (SI) estimated using Modified Model for OGTT analysis: P = 0.03 Mathur R et al, ADA 2014 Weight (g) M. Smithii and Obesity in Rat model Number of segments with no M. smithii Mathur R et al, Obesity, 2013 ΔCH min Normalized to Control SYN-010: Most Effective CH 4 Inhibitor In Vitro Figure 1: Effect of marketed statins on CH 4 production in stool from IBS-C patients *5 mg statin/g wet stool. Data are change in CH 4 (ppm) from baseline to 270 min; normalized to control (100) Control Statin 1 Statin 2 Statin 3 Statin 4 Statin 5 70 NYSE MKT: SYN Breath CH 4 (ppm) SYN-010 Clinical Validation Figure 3: Reduction of breath CH 4 in an IBS-C patient by Statin 1 but not Statin Statin 2: No effect No Statin : CH 4 returns Statin 1 Form 1 Modest efficacy 20 0 No Statin Statin 2 Statin 1 Form 1 Statin 1 Form 1 + Form 2 CH 4 = 0 ppm Statin 1 Form 1 No Statin Statin 1 Form 2 Statin 1 Form 1 + Form 2 No bloating 1 BM per day Lovastatin: Effect on M. smithii and constipation Morales, et al DDW 2015 % Stool Wet Weight High fat diet leads to Constipation P Baseline 7 Weeks HF Morales, et al DDW 2015 M. smithii (cfu/g tissue) Total Bacteria (cfu/g tissue) SYN-010 is NOT Microbicidal Figure 2: Effect of Statin 1 on levels of M. smithii and total bacteria in the rat GI tract after 10 days oral gavage dosing M. smithii Total bacteria 3.5E E+06 Placebo Statin 1 (1 mg/kg) 7.0E E+07 Placebo Statin 1 (1 mg/
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