NYSE MKT: SYN Microbiome Analyst & Investor Meeting New York - - PowerPoint PPT Presentation

June 3, 2015

NYSE MKT: SYN Microbiome Analyst & Investor Meeting New York City

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

• r 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

• btain or maintain the capital or grants necessary to fund our research and development activities, a loss of any of
• ur 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

• 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

Agenda

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

4

* Effective June 22, 2015

Investment Proposition

• 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

NYSE MKT: SYN

5

Microbiome Product Pipeline

C - Cedars-Sinai Medical Center collaboration

Completed Planned – 2015

6

Therapeutic Area Product Candidate Biologic Agent/ Drug Compound Discovery Preclinical Phase 1 Phase 2 Phase 3

• C. difficile infection/

Antibiotic- associated diarrhea (AAD) SYN-004 Oral enzyme Irritable bowel syndrome with constipation (IBS-C) SYN-010 C Oral drug

Mar 2015

• C. difficile

Positive PK data from Phase 1a and 1b clinical trials

Feb 2015

IBS-C SYN-010 modified-release formulation of Lovastatin

Feb 2015

• C. difficile

Positive topline results from Phase 1b clinical trial

Dec 2014

• C. difficile

Initiated Phase 1a and 1b clinical trials

Dec 2014

• C. difficile

Positive topline results from Phase 1a clinical trial

Nov 2014

• C. difficile

First SYN-004 U.S. composition

• f matter patent; adds to

extensive C. difficile patent estate

Key Microbiome Achievements

Mar 2015

• C. difficile

Initiated Phase 2a clinical trial

7

Upcoming Microbiome Milestones

8

2H 2015

• C. difficile

Report topline data from Phase 2b clinical trial

2H 2015

IBS-C Report topline data from Phase 2 clinical trial

3Q 2015

• C. difficile

Initiate Phase 2b clinical trial

2Q 2015

• C. difficile

Report topline data from Phase 2a clinical trial

2Q 2015

IBS-C Initiate Phase 2 clinical trials

2Q 2015

IBS-C Submit IND to support clinical trials

2016

IBS-C & C. difficile Initiate Pivotal Phase 3 clinical trials

Human Microbiome

The Body Has 10 Times as Many Microbe Cells as Human Cells

9

Source: http://commonfund.nih.gov/hmp/overview.aspx

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

Diseases Directly Influenced by the Gut Microbiome

10

Source: Genome Medicine 2011, 3:14 http://genomemedicine.com/content/3/3/14

Human Microbiome Over Time

Response to Environmental Conditions and Life Stages

11

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. 2:104.

Joe Sliman, M.D., MPH

Senior Vice President, Clinical & Regulatory Affairs

12

• 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

Klaus Gottlieb, M.D., FACG

• Quintiles

̶ Gastroenterology Therapeutic Area Lead

• USFDA

̶ 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

New Clinical & Regulatory Team Member

13

Microbiome Analyst & Investor Meeting New York City Irritable Bowel Syndrome with Constipation (IBS-C) Mark Pimentel, M.D., FRCP(C)

Mark Pimentel, M.D., FRCP(C)

IBS-C Keynote Speaker

15

• 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

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

*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;130:1480-1491.

IBS-C IBS-U IBS-M IBS-D

25 50 75 100 25 50 75 100

Loose or Watery Stools, % Hard or Lumpy Stools, %

Type 6* Type 2* Type 1*

IBS Subtypes Based on Stool Form

18

Loperamide Diphenoxylate Alosetron Cholestyramine Antibiotics

Diarrhea

Fiber Osmotic and stimulant laxatives Lubiprostone

Constipation

Antispasmodics Antidepressants Alosetron Antibiotics Probiotics

Abdominal pain/ discomfort Bloating

Camilleri M. Gastroenterology. 2001;120:652-668. Drossman DA, et al. Gastroenterology. 2002;123:2108-2131. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.

Drug Therapy

Non-Constipation-IBS

D-IBS M-IBS C-IBS

Antidepressant Action Visceral Analgesia Changes in Motility Smooth Muscle Relaxation (TCA)

TCA=tricyclic antidepressants. Adapted from Rome Foundation Functional GI Disorders Specialty Modules.

Tricyclic Antidepressants and IBS

5 10 15 20 25 30 35 40 45 50 1 2 3 4 5 6 7 8 9 10

Placebo Rifaximin

*P=0.02 Mixed Longitudinal Model for 10-week difference

Percent Global Improvement

Weeks after Rifaximin

Pimentel, et al, Ann Intern Med, 2006

Rifaximin: First Controlled Trial

IBS Bloating Weekly SGA-IBS Weekly Efficacy Outcome

0.0002 (1.23,1.96) 1.56 Combined 0.0167 (1.08,2.06) 1.49 TARGET 2 0.0045 (1.16,2.27) 1.62 TARGET 1 0.0008 (1.18,1.88) 1.49 Combined 0.0263 (1.05,2.01) 1.45 TARGET 2 0.0125 (1.10,2.12) 1.53 TARGET 1

p-value (95% CI) Odds Ratio Study IBS Bloating Weekly SGA-IBS Weekly Efficacy Outcome

0.0002 (1.23,1.96) 1.56 Combined 0.0167 (1.08,2.06) 1.49 TARGET 2 0.0045 (1.16,2.27) 1.62 TARGET 1 0.0008 (1.18,1.88) 1.49 Combined 0.0263 (1.05,2.01) 1.45 TARGET 2 0.0125 (1.10,2.12) 1.53 TARGET 1

p-value (95% CI) Odds Ratio Study

Key Secondary Primary

Odds Ratio and 95% CI

0.0 0.5 1.0 1.5 2.0 2.5

Favors Placebo Favors Rifaximin

0.0009 (1.17,1.84) 1.47 Combined 0.0077 (1.12,2.13) 1.55 TARGET 2 0.0401 (1.02,1.92) 1.40 TARGET 1

Ab Pain & Stool Daily (FDA) Stool Consist. Daily (FDA) Ab Pain Daily (FDA)

<0.0001 (1.31,2.14) 1.67 Combined 0.0096 (1.12,2.21) 1.57 TARGET 2 0.0015 (1.25,2.59) 1.80 TARGET 1 0.0009 (1.17,1.83) 1.46 Combined 0.0194 (1.06,2.00) 1.46 TARGET 2 0.0157 (1.08,2.03) 1.48 TARGET 1 0.0009 (1.17,1.84) 1.47 Combined 0.0077 (1.12,2.13) 1.55 TARGET 2 0.0401 (1.02,1.92) 1.40 TARGET 1

Ab Pain & Stool Daily (FDA) Stool Consist. Daily (FDA) Ab Pain Daily (FDA)

<0.0001 (1.31,2.14) 1.67 Combined 0.0096 (1.12,2.21) 1.57 TARGET 2 0.0015 (1.25,2.59) 1.80 TARGET 1 0.0009 (1.17,1.83) 1.46 Combined 0.0194 (1.06,2.00) 1.46 TARGET 2 0.0157 (1.08,2.03) 1.48 TARGET 1

FDA Proposed

IBS Ab Pain Daily IBS Bloating Daily SGA-IBS Daily

0.0028 (1.13,1.78) 1.42 Combined 0.0232 (1.05,2.03) 1.46 TARGET 2 0.0255 (1.05,2.02) 1.45 TARGET 1 0.0004 (1.21,1.92) 1.52 Combined 0.0008 (1.26,2.44) 1.76 TARGET 2 0.0486 (1.01,1.97) 1.41 TARGET 1 <0.0001 (1.28,2.04) 1.61 Combined 0.0072 (1.13,2.24) 1.59 TARGET 2 0.0009 (1.26,2.47) 1.76 TARGET 1

IBS Ab Pain Daily IBS Bloating Daily SGA-IBS Daily

0.0028 (1.13,1.78) 1.42 Combined 0.0232 (1.05,2.03) 1.46 TARGET 2 0.0255 (1.05,2.02) 1.45 TARGET 1 0.0004 (1.21,1.92) 1.52 Combined 0.0008 (1.26,2.44) 1.76 TARGET 2 0.0486 (1.01,1.97) 1.41 TARGET 1 <0.0001 (1.28,2.04) 1.61 Combined 0.0072 (1.13,2.24) 1.59 TARGET 2 0.0009 (1.26,2.47) 1.76 TARGET 1

Other Secondary

Primary Outcome (4 weeks after Tx)

Pimentel, et al NEJM, 2011

Favors Placebo Favors Rifaximin Odds Ratio and 95% CI

0.0014 (1.14, 1.72) 1.40 Combined 0.0141 (1.08, 1.92) 1.44 TARGET 2 0.0396 (1.01, 1.83) 1.36 TARGET 1

Ab Pain & Stool Daily (FDA) IBS Bloating Weekly p-value (95% CI) Odds Ratio Study Efficacy Outcome

<0.0001 (1.27, 1.97) 1.58 Combined 0.0114 (1.09, 2.00) 1.48 TARGET 2

Stool Consist. Daily (FDA)

0.0009 (1.24, 2.33) 1.70 TARGET 1 0.0058 (1.09, 1.64) 1.33 Combined 0.0298 (1.03, 1.83) 1.37 TARGET 2 0.0725 (0.98, 1.75) 1.31 TARGET 1

Ab Pain Daily (FDA)

0.0118 (1.06, 1.61) 1.31 Combined 0.0435 (1.01, 1.81) 1.35 TARGET 2

IBS Ab Pain Daily

0.0495 (1.00, 1.83) 1.35 TARGET 1 <0.0001 (1.24, 1.89) 1.53 Combined 0.0008 (1.24, 2.25) 1.67 TARGET 2 0.0103 (1.10, 2.04) 1.50 TARGET 1

IBS Bloating Daily

0.0003 (1.20, 1.83) 1.48 Combined 0.0127 (1.09, 1.99) 1.47 TARGET 2

SGA-IBS Daily

0.0025 (1.18, 2.18) 1.60 TARGET 1 0.0011 (1.15, 1.75) 1.42 Combined 0.0031 (1.16, 2.09) 1.56 TARGET 2 0.1042 (0.95, 1.73) 1.28 TARGET 1 0.0007 (1.17, 1.77) 1.44 Combined 0.0053 (1.13, 2.03) 1.52 TARGET 2

SGA-IBS Weekly

0.0477 (1.00, 1.82) 1.35 TARGET 1 0.0014 (1.14, 1.72) 1.40 Combined 0.0141 (1.08, 1.92) 1.44 TARGET 2 0.0396 (1.01, 1.83) 1.36 TARGET 1

Ab Pain & Stool Daily (FDA) IBS Bloating Weekly p-value (95% CI) Odds Ratio Study Efficacy Outcome

<0.0001 (1.27, 1.97) 1.58 Combined 0.0114 (1.09, 2.00) 1.48 TARGET 2

Stool Consist. Daily (FDA)

0.0009 (1.24, 2.33) 1.70 TARGET 1 0.0058 (1.09, 1.64) 1.33 Combined 0.0298 (1.03, 1.83) 1.37 TARGET 2 0.0725 (0.98, 1.75) 1.31 TARGET 1

Ab Pain Daily (FDA)

0.0118 (1.06, 1.61) 1.31 Combined 0.0435 (1.01, 1.81) 1.35 TARGET 2

IBS Ab Pain Daily

0.0495 (1.00, 1.83) 1.35 TARGET 1 <0.0001 (1.24, 1.89) 1.53 Combined 0.0008 (1.24, 2.25) 1.67 TARGET 2 0.0103 (1.10, 2.04) 1.50 TARGET 1

IBS Bloating Daily

0.0003 (1.20, 1.83) 1.48 Combined 0.0127 (1.09, 1.99) 1.47 TARGET 2

SGA-IBS Daily

0.0025 (1.18, 2.18) 1.60 TARGET 1 0.0011 (1.15, 1.75) 1.42 Combined 0.0031 (1.16, 2.09) 1.56 TARGET 2 0.1042 (0.95, 1.73) 1.28 TARGET 1 0.0007 (1.17, 1.77) 1.44 Combined 0.0053 (1.13, 2.03) 1.52 TARGET 2

SGA-IBS Weekly

0.0477 (1.00, 1.82) 1.35 TARGET 1

Key Secondary Primary Other Secondary FDA Proposed

0.0 0.5 1.0 1.5 2.0 2.5

Durability of Response (3 months)

Pimentel, et al NEJM, 2011

Constipation-IBS

D-IBS M-IBS C-IBS

Study (Year, Drug, Dose) Treatment n/N Control n/N RR (Random) 95% CI Kuiken (2003, fluoxetine 20 qd) 9/19 12/21 Tabas (2004, paroxetine 10-40 qd) 25/44 36/46 Vahedi (2005, fluoxetine 20 qd) 6/22 19/22 Tack (2006, citalopram 20-40 qd) 5/11 11/12 Talley (2008, citalopram 40 qd) 5/17 5/16 Subtotal (95% CI) 113 117

RR=0.62 (95% CI=0.45-0.87) NNT=3.5

0.2 0.5 1 2 5 Favors Treatment Favors Control 0.1 10

*Significant heterogeneity among studies may limit conclusions. Study duration ranged from 6 weeks to 12 weeks. Ford AC, et al. Gut. 2009;58:367-378. 26

SSRI – Meta-analysis

Lubiprostone for IBS-C: Data From Two Phase 3 Trials

• 12-week treatment period
• Overall responder: Monthly

responder for at least 2 of 3 months

• Monthly responder: At least

moderate relief for 4/4 weeks

• r significant relief for 2/4

weeks

17.9 10.1 25 50 Lubiprostone 8 µg BID Placebo Overall Responders (%) *P=.001 N=780 N=387

Drossman DA et al. Aliment Pharmacol Ther. 2009;29:329-341.

Lubiprostone: Adverse Effects

Drossman DA et al. Aliment Pharmacol Ther. 2009;29:329-341.

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%

18.2 15.6 14.1 33.8 36.7 33.2 10 20 30 40 50 60 70 % Responders

≥6/12 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%

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 Phase 3 Studies in IBS-C: EMA Analysis

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%)

Linaclotide in IBS-C Phase 3 Trial: Safety

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):3503-6. Eradication of small intestinal bacterial

• vergrowth reduces symptoms of

irritable bowel syndrome.

Human Cells

Bacterial Cells

Number of Cells

100x more Bacterial cells

Kingdoms of Life

Eukaryotes Bacteria Archaea Example: Plants and animals Example: Salmonella,

• E. coli

Example: Methanogens

SIBO- What is it?

1011cfu/mL 103 cfu/mL 102 cfu/mL Colon

Small Bowel

101 cfu/mL ~ 0 cfu/mL

Duodenum Cecum Jejunum Ileum

Type of Test Specific Test Breath testing Lactulose Breath Test 13C Xylose Breath Test Glucose Breath Test Sucrose Breath Test Sorbitol Breath Test Culture Small bowel aspirate and culture Empiric Approach Test, treat and re-evaluate

Different Approaches to SIBO

Non-Constipation-IBS

D-IBS M-IBS C-IBS

NOTE: Weights are from random effects analysis

Overall (I-squared = 67.9%, p = 0.008) Parodi Scarpellini Lupascu Author Collin Pimentel Grover glucose lactulose glucose Breath Test lactulose Type of lactulose sucrose

9.64 (4.26, 21.82) 4.30 (1.24, 14.98) 24.27 (7.35, 80.15) 10.89 (3.52, 33.71) OR (95% CI) 18.04 (6.55, 49.71) 20.67 (5.29, 80.69) 2.29 (0.89, 5.87) 100.00 15.71 16.20 16.82 Weight 17.94 % 14.68 18.65

9.64 (4.26, 21.82) 4.30 (1.24, 14.98) 24.27 (7.35, 80.15) 10.89 (3.52, 33.71) OR (95% CI) 18.04 (6.55, 49.71) 20.67 (5.29, 80.69) 2.29 (0.89, 5.87) 100.00 15.71 16.20 16.82 Weight 17.94 % 14.68 18.65 1 .1 .2 .5 1 2 5 10 20

Forest plot of all age-sex matched studies Shah, et al Dig Dis Sci, 2010

Breath Testing is abnormal in IBS

5 10 15 20 25 30 35 40 45 50 >10,000 coliforms >5,000 coliforms Percent of Subjects

Control IBS 4% 24% 12% 43% N=165 IBS, 26 controls Posserud, et al, Gut, 2007;56:802-8.

P<0.05 P<0.001

Small Bowel Culture in IBS

SIBO and IBS

10 20 30 40 50 60 70 Percent of Subjects

Non- D-IBS D-IBS 27.3% 60% N=77 non-D-IBS, N=35 D-IBS

P=0.004

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

Constipation-IBS

D-IBS M-IBS C-IBS

Hydrogen Producers H2S Producers 5H2→1H2S Methane Producers 4H2→1CH4

H2 H2

Complexities of Gas Production

Methane in C-IBS

10 20 30 40 50 60 70 80 90 100 H2 CH4 and H2 CH4 % of patients Constipation Diarrhea

X2=16.6, p<0.001

Pimentel, et al. Dig Dis Sci, 2003.

20 40 60 80

Room Air Methane

% Marker Recovery

Pimentel, et al. Am J Physiol, 2006. n=5, p<0.0001 69% mean slowing

• f transit with CH4

Methane Slows Intestinal Transit

Kunkel, et al. Dig Dis Sci, 2011.

NOTE: Weights are from random effects analysis

Overall (I-squared = 64.6%, p = 0.004) Pimentel Hwang Pimentel Majewski Bratten Attaluri Fiedorek Parodi Peled Author 2003 2009 2003 2007 2008 2009 1990 2009 1987 Year

3.51 (2.00, 6.16) 5.58 (2.22, 14.03) 47.67 (8.73, 260.41) 44.23 (2.48, 788.51) 1.81 (0.70, 4.67) 2.22 (1.14, 4.33) 3.70 (2.06, 6.66) 4.32 (1.60, 11.68) 1.89 (0.79, 4.51) 0.83 (0.20, 3.56) OR (95% CI) 100.00 12.68 6.99 3.18 12.46 15.14 15.92 12.03 % 13.17 8.43 Weight

1 .1 .2 .5 1 2 5 10 20

Meta-analysis of studies

Methane- Important in C-IBS

Methanobrevibacter smithii

• M. smithii is the predominant

human methanogen

• There are no drug

development plans around the

• rganism
• This organism is important in

health and disease

Methane Factor Analysis

• Constipation
• lack of milk intolerance
• lack of weight loss
• small bowel movements
• straining

After treatment constipation level by group

10 20 30 40 50 60

Neo+plac Neo+rifax P=0.01 VAS score

Pimentel, et al. Dig Dis Sci, 2014.

After treatment bloating level by group

10 20 30 40 50 60 70 Neo+plac Neo+rifax P<0.01 VAS score

Pimentel, et al. Dig Dis Sci, 2013.

Weekly Constipation VAS

10 20 30 40 50 60 70 80

Pre Tx Post Tx 1 2 3 4

Neo+plac Neo+rifax

* + ¶

*P=0.01 ¶P<0.01 +P=0.14

¶ ¶

VAS Constipation Severity

Pimentel, et al. ACG, 2013.

Weekly Bloating VAS

10 20 30 40 50 60 70 80 Pre Tx Post Tx 1 2 3 4

Neo+plac Neo+rifax

* ¶

*P<0.05 ¶P=NS

¶ VAS Bloating Severity * * Pimentel, et al. Dig Dis Sci, 2014.

Weekly Abdominal Pain VAS

5 10 15 20 25 30 35 40 45 50 Pre Tx Post Tx 1 2 3 4

Neo+plac Neo+rifax VAS Abdominal Pain Severity

Pimentel, et al. ACG, 2013.

Final visit constipation severity based on methane >3ppm

10 20 30 40 50 60 70 80 Methane >3ppm Methane <3ppm P=0.04

VAS score Analysis of the Neomycin + Rifaximin Group

Pimentel, et al. Dig Dis Sci, 2014.

OBESITY DIABETES Cultural Social Psychiatric Meds Genetics Environmental Psychological GI MICROBES

Methanogen Model- Syntropic Effect

Indigestible Substrate

H2

Intoxicates self = Syntroph = Methanogen

Indigestible Substrate

H2 H2 H2 H2

CH4

Energy Digestible Substrates for Host

Energy

Digestible Substrates for Host

Methanobrevibacter smithii

20 40 60 80

Room Air Methane

% Marker Recovery

Pimentel, et al. Am J Physiol, 2006.

n=5, p<0.0001 69% mean slowing

• f transit with CH4

Methane Slows Transit

Methane in Obese Patients

Mathur et al, Gastro and Hep, 2012

N=58 No Methane

• n Breath

(n=46) Positive Methane on breath (n=12) P-value Age (yrs) 41.8+1.4 41.9 + 1.6 41.6 + 3.3 0.933 Height (in) 66.7 + 0.6 66.5 + 0.7 67.7 +1.4 0.373 Weight (lbs) 255 + 8.0 242.3 + 7.1 299.0 + 22.7 0.002 34 36 38 40 42 44 46

BMI

All Subjects No Methane Positive Methane

P= 0.001

Methane in Non-obese Patients

20 22 24 26 28 30 32 34 36 38 40 Normal Breath test Positive Hydrogen Breath Test Methane Only Methane and Hydrogen Positive

Multivariate analysis controlling for age, sex , diabetes, anti depressant and other confounding (P<0.001) N=792

BMI

Mathur et al. JCEM 98:E698-702, 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 (35.2 + 7.7 kg/m2) methane positive subjects aged 47 + 9 years (funded by the ADA)

Mathur R et al, ADA 2014

Mathur R et al, ADA 2014

Mathur R et al, ADA 2014

P = 0.03

Insulin Sensitivity (SI) estimated using Modified Model for OGTT analysis:

Mathur R et al, ADA 2014

• M. Smithii and Obesity in Rat model

Mathur R et al, Obesity, 2013 270 280 290 300 310 320 330 1 2 3 Weight (g) Number of segments with no M. smithii

70

• 80
• 60
• 40
• 20

20 40 60 80 100 120 Control Statin 1 Statin 2 Statin 3 Statin 4 Statin 5

ΔCH4 0-270 min Normalized to Control

SYN-010: Most Effective CH4 Inhibitor In Vitro

NYSE MKT: SYN

Figure 1: Effect of marketed statins on CH4 production in stool from IBS-C patients

*5 mg statin/g wet stool. Data are change in CH4 (ppm) from baseline to 270 min; normalized to control (100)

SYN-010 Clinical Validation

20 40 60 80 100 120 140 No Statin Statin 2 Statin 1 Form 1 Statin 1 Form 1 No Statin Statin 1 Form 2 Statin 1 Form 1 + Form 2

Breath CH4 (ppm)

Figure 3: Reduction of breath CH4 in an IBS-C patient by Statin 1 but not Statin 2 Statin 1 Form 1 Modest efficacy No bloating 1 BM per day Statin 2: No effect Statin 1 Form 1 + Form 2 CH4 = 0 ppm No Statin : CH4 returns

Morales, et al DDW 2015

Lovastatin: Effect on M. smithii and constipation

40 60 80 100 Baseline 7 Weeks HF % Stool Wet Weight

P<0.01

High fat diet leads to Constipation

Morales, et al DDW 2015

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

• M. smithii (cfu/g tissue)

Rat tissue Placebo Statin 1 (1 mg/kg)

Total Bacteria (cfu/g tissue) Rat tissue Placebo Statin 1 (1 mg/kg)

40 45 50 55 60 65 70 Day 0 Day 14 Day 61 Day 70 Day 10 Gavage % Stool Wet Weight Water Lovastatin Lactone Lovastatin Hydroxy Acid

Morales, et al DDW 2015

Conclusions for Methane

• Methane is a biomarker for constipation and

C-IBS

• The degree of methane production is

proportional to constipation severity in C-IBS

• Methane infusion in the gut slows transit
• Methane reduction is linked to improved

constipation

Conclusions for M. smithii

• M. smithii is the primary methanogen in

humans

• M. smithii is distributed throughout the gut in

humans and rodents

• M. smithii colonization is linked to greater

methane production

• Degree of M. smithii colonization is linked to

greater constipation in C-IBS

Conclusions for Statins in Microbiome directed therapy of methanogens

• A key statin strategy inhibits the

methanogenesis pathway

• Not all statins are the same
• The key statin strategy appears most effective

at inhibiting methane production in vitro and in humans

• Lovastatin improves stool wet weight.

Projected Number of IBS-C Patients in the US to 2023

USA 2015 2017 2019 2020 2023 Prevalence of IBS 17,495,748 17,762,842 18,024,741 18,283,624 18,569,127 IBS-C Cases 20% incidence 3,499,150 3,552,568 3,604,948 3,656,725 3,713,825 Diagnosed IBS-C Cases 1,049,745 1,065,771 1,081,484 1,097,017 1,114,148 IBS-C Cases on therapy 734,821 746,039 757,039 767,912 779,903

Prevalent Cases from: GlobalData PharmaPoint, Irritable Bowel Syndrome – Global Drug Forecast and Market Analysis to 2023

• 30% of patients with IBS have a proper IBS diagnoses
• Opportunity to increase disease state awareness and treatment options.
• 70% of IBS diagnosed patients in US are on pharmacotherapy
• IBS-C makes up 20% of the IBS overall prevent cases
• Projected growth rate of the P\prevalence of IBS from 2015 to 2023 is est. 6-7%

The IBS Market has Significant Unmet Needs

80

Source: GlobalData PharmaPoint, IBS Global Drug Forecast & Market Analysis 2014

New products with improved efficacy Products that effectively address IBS symptoms, such as abdominal pain and bloating Improved diagnosis of IBS/definitive test or biomarker

• IBS patients are underserved with current therapies that show only modest

efficacy or are associated with negative safety profiles

• Diagnosis and drug-treatment rates for IBS remain low across the major markets
• The prescription IBS market is poised for significant growth through 2021, given

these unmet needs

SYN-010 for IBS-C

Clinical development plan

• Phase 2 study start expected 2Q ‘15
• 1st study: Demonstrate reduction of breath methane in IBS-C

patients using SYN-010 ̶ 60 subjects, all diagnosed IBS-C, breath methane > 10ppm ̶ 2 doses of SYN-010 daily vs placebo, 4 weeks of treatment ̶ Endpoints

• Primary: Reduction of breath methane after 4 weeks of therapy
• Secondary 1: Improvement in number of complete spontaneous

bowel movements per week (required per FDA guidance)

• Secondary 2: Improvement in abdominal pain and bloating per

standard scales (required per FDA guidance)

81

SYN-010 for IBS-C

Clinical development plan

• 2nd study: Demonstrate maintenance of reduction of breath

methane in same IBS-C patients using SYN-010 ̶ 60 subjects from the previous study (rollover) ̶ Open label, higher dose of SYN-010 daily, 8 weeks of treatment ̶ Endpoints

• Primary: Maintenance of breath methane reduction after 8 weeks of

therapy

• Analysis of improvement after 8 weeks for subjects who were on

placebo or low-dose therapy in the first study

• Secondary: CSBMs & abdominal pain per FDA guidance
• Results expected Q4 ‘15

82

SYN-010 for IBS-C

Clinical development plan: Phase 3

• Pursue Phase 3 clinical trial(s) (2016) following discussions with FDA
• Objectives: standard IBS-C by-guidance FDA endpoints (CSBMs and abdominal

pain and bloating)

• Patients: all patients with diagnosed IBS-C regardless of breath methane

status

• Breath methane to be utilized as a mechanistic secondary endpoint, but

not as a screen for patients

• Expected: Single large Phase 2b/3 (dose-ranging and final formulation), 12

weeks of therapy daily

• Rationale: no safety issues (lovastatin safety profile is well-defined)
• 505(b)2 NDA pathway
• Given standardized endpoints, one large, adequately-powered study

should be sufficient for registration

83

Microbiome Analyst & Investor Meeting New York City Irritable Bowel Syndrome with Constipation (IBS-C) SYN-010 Animated Video

Microbiome Analyst & Investor Meeting New York City Irritable Bowel Syndrome with Constipation (IBS-C) Q&A Session

Microbiome Analyst & Investor Meeting New York City

• C. difficile

Professor Mark H. Wilcox, M.D., FRCPath

Professor Mark H. Wilcox, M.D., FRCPath

• C. difficile Keynote Speaker

87

• Consultant / Head of Microbiology, Leeds Teaching Hospitals NHS Trust
• Professor of Medical Microbiology, University of Leeds
• Lead on C. difficile Infection, Public Health England
• Chairman of Synthetic Biologics’ C. difficile Clinical Advisory Board

• C. difficile INFECTION (CDI)

CLINICAL IMPACT & NOVEL WAY TO PREVENT

PROFESSOR MARK WILCOX, MD

Chair of Clinical Advisory Board, Synthetic Biologics, Inc. Leeds Teaching Hospitals, University of Leeds, & Public Health England, UK

Preventing C. difficile Is Now a National Priority!

90

Source: https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf

2015 2020

National Action Plan for Combating Antibiotic Resistance Issued By the White House in March 2015

• Goal is to reduce the incidence of overall C. difficile infection by 50%

compared to rates in 2011

• Implementation of plan and tracking of outcomes will accomplished by

several government agencies

• C. difficile infections
• CDI is currently the most prevalent hospital-acquired infection in the

U.S., according to the CDC

̶ Surpassed Methicillin-resistant Staphylococcus aureus (MRSA)

• CDI has been identified as an “urgent public health threat” by the

CDC, FDA and EU health authorities

• CDI in the U.S.:

̶ 1.1 million patients infected with C. difficile annually1 ̶ Patients with C. difficile hospitalized approximately 4-7 extra days2 ̶ Up to ~25% of CDI patients have a recurrence within 1-3 months3-5 ̶ $8.2 billion in costs associated with C. difficile-related stays in hospital6 ̶ >30,000 C. difficile-related deaths annually7

database for full year 2012. IMS expressly reserves all rights, including rights of copying, distribution and republication.

• 2009. January 2012.

EUropean, multi-centre, prospective bi-annual point prevalence study of CLostridium difficile Infection in hospitalised patients with Diarrhoea Study initiated and financially supported by Astellas Pharma Europe Ltd

• Largest CDI epidemiology

study ever conducted

• 20 countries across Europe

~500 hospitals

EUCLID key findings - Conclusions Rates of CDI in EUCLID were 70% higher than seen in 2008 1,2 An estimated 39,000+ cases of CDI are missed every year in Europe – over 80 cases per hospital per year 1

• 1. Davies KA, et al. Lancet Infect Dis 2014;14:1208-19.
• 2. Bauer MP, et al. Lancet 2011;377:63–73.

Who is most at risk?

Recent antibiotic use Elderly

Bauer MP, et al. Lancet 2011; 377:63–73

Chronic illness

ECDC, European Centre for Disease Prevention and Control

75 yrs

• ld

pvd ?pneumonia CDI

Length of hospital stay in patients with CDI by country

Wiegand PN, et al. J Hosp Infect 2012;81:1–14. EU, European Union

45 40 35 20 10 Length of stay (days) 25 30 15 5 16 17 17 12 15 50 27 21 18 37 Country

30-day mortality in patients with healthcare facility-acquired CDI

Wiegand PN, et al. J Hosp Infect 2012;81:1–14.

45 40 35 20 10 30-day mortality (%) 25 30 15 5 14% 16% 14% 3% 16% 7% 15% 22% 9% 20% 30% Country

Strain ribotype and age-related risk of CDI mortality

Miller M, et al. Clin Infect Dis 2010;50:194–201.

Age (years)

p=NS p=0.02 p=0.07 p=0.005

2 4 6 8 10 12 14 16 18 18–39 40–49 50–59 60–69 70–79 80–89 90+ CDI-related death (%) NAP1/027 Non-NAP1 CD 027 infection associated with 2.5 to 3.5-fold increased death rate n=1,008 CDI cases

CD, Clostridium difficile; NS, not significant

p=NS p=NS p=NS

CDI case costs

• 1. Adapted from Ghantoji SS, et al. J Hosp Infect 2010;74:309–18;
• 2. Vonberg R-P, et al. J Hosp Infect 2008;70:15–20.

10,000 20,000 30,000 40,000 50,000 60,000 Ananthakrishnan (IBD patients) Dubberke (primary admission) Dubberke (inpatient over 180 days) Kyne (inpatients only) Lawrence (ICU stay only) Lawrence (hospital-wide) O´Brien (secondary diagnosis) Vonberg (hospital-wide) Zerey (surgical inpatients)

*Data from the last 10 years; IBD, inflammatory bowel disease; ICU, intensive care unit

Case cost* (2008 € equivalent)

1 1 1 1 1 1 1 1 2

Who is most at risk?

Recent antibiotic use Elderly

Bauer MP, et al. Lancet 2011; 377:63–73

Chronic illness

ECDC, European Centre for Disease Prevention and Control

Role of microbiome in human health

• Inflammatory bowel diseases
• Metabolic disorders, diabetes
• Hypertension
• Obesity
• Cancer
• Infection

particularly C. difficile infection

Colonisation resistance

anaerobes aerobes

aerobes Clostridium difficile

% %

Scissoracillin

Colonisation resistance in real patients

aerobes Clostridium difficile

%

Scissorcillin 3

%

Resistance emergence

anaerobes aerobes

aerobes Clostridium difficile

%

Scissorcillin 2 Resistance emergence

anaerobes aerobes

aerobes Clostridium difficile

%

Scissorcillin 4 Resistance emergence

% % %

Scissoracillin Scissoracillin Scissoracillin

% %

Antibiotics and risk of CDI

Evidence to support the restriction of these as control measure for CDI CDI may still occur !

High risk Medium risk Low risk ampicillin/amoxy co-trimoxazole macrolides fluoroquinolones aminoglycosides metronidazole anti-pseudomonal penicillins +

B-lactamase inhibitor

tetracyclines rifampicin vancomycin cephalosporins clindamycin

Multiple antibiotics and CDI risk

Number of antibiotics Adjusted hazard ratio for CDI 1

• 2

2.5 3 or 4 3.3 >5 9.6

Stevens V, et al. Clin Infect Dis 2011;53:42-8.

database for full year 2012. IMS expressly reserves all rights, including rights of copying, distribution and republication.

24 million patients are administered IV antibiotics annually in the U.S.1

SYN-004: Market Potential

Intended to target certain IV β-lactam antibiotics

~14M patients11 ~27M prescriptions10

~118M doses

• f “SYN-004 target”

antibiotics purchased by U.S. hospitals to fill patient prescriptions9

* Based on U.S. market data in 2012 ** Estimate based on the following assumptions: 5 day prescription x 4 “SYN-004 tablets”/day x $25/”SYN-004 tablet” x 26.5M prescriptions of “SYN-004 target” β-lactam antibiotics in 2012

• 2012. IMS expressly reserves all rights, including rights of copying, distribution and republication.

SYN-004 Potential U.S. Market

~$13 Billion **

*

108

Paradigm Shift

Fewer CDIs expected with co-administration of SYN-004

Antibiotics Treatments

• β-lactam
• Fluoroquinolone
• Clindamycin
• Other
• Metronidazole
• Vancomycin
• Fidaxomicin

Current Paradigm

• C. difficile

Infections (CDI)

Paradigm Shift

Fewer CDIs expected with co-administration of SYN-004

Antibiotics Treatments

• β-lactam
• Fluoroquinolone
• Clindamycin
• Other
• Metronidazole
• Vancomycin
• Fidaxomicin

Current Paradigm SYN-004 Paradigm

• C. difficile

Infections (CDI)

SYN-004 + β-lactam Antibiotics*

SYN-004 designed to protect the natural balance

• f the gut microbiome during antibiotic use

PREVENTION

* Intended to include penicillins plus cephalosporins

Concept Validated by 1st Generation Candidate

Positive Phase 1 & 2 clinical data

• 1st generation candidate (P1A) was studied in four Phase 1 and one

Phase 2 clinical trials conducted in Europe

• 112 patients and 143 healthy normal subjects
• Well tolerated with no safety concerns identified
• Antibiotic-associated diarrhea (AAD) occurrence prevented
• Preserved the normal intestinal microflora when co-administered

with IV ampicillin or piperacillin

• Did not alter the PK profile of IV piperacillin or ampicillin (or

efficacy of ampicillin in patients with respiratory infections)

• Original technology developed by Finnish biotechnology company,

Ipsat Therapies Oy, along with 2nd generation enzyme, SYN-004

SYN-004

Clinical trial development

• Completed Phase 1a (40 participants) and 1b

(24 participants) trials

̶ PK data supports that SYN-004 should have no effect on the IV antibiotic in the bloodstream ̶ No clinically significant safety events were observed; well tolerated by participants

• Phase 2a studies ongoing

̶ Characterize SYN-004 activity on ceftriaxone in the small intestine ̶ Demonstrate SYN-004 has no activity on ceftriaxone in the bloodstream ̶ Topline data expected 2Q ‘15

SYN-004

Clinical trial development: Phase 2b Objectives:

• Study initiation expected 3Q ’15

̶ FDA has reviewed and approved study endpoints and inclusion criteria ̶ Demonstrate SYN-004 efficacy at preventing C. difficile-associated diarrhea (CDAD) and antibiotic-associated diarrhea (AAD) following IV ceftriaxone ̶ Demonstrate SYN-004 efficacy at limiting disruption of the gut microbiome by IV ceftriaxone ̶ Enrolling 180-600 patients, diagnosed lower respiratory tract infection, admitted for IV ceftriaxone therapy, at high-risk for C. diff ̶ 65 years old and older, recent hospitalization, IV beta-lactam therapy ̶ CDC data confirms these are the highest risk groups for C. diff ̶ 75 sites in US/Canada/Eastern Europe ̶ Rationale: Similar standards for antibiotic therapies, similar C. diff rates

SYN-004

Clinical trial development: Phase 2b Analysis

• Interim data expected Q4 ’15

̶ Review of first 30% of patients, to ensure baseline rate of CDI is high enough to ensure adequate study power ̶ Review interim efficacy, potential combination antibiotic therapies for sub-analysis ̶ Review CDI rates by sites (US/Canada vs Eastern Europe) ̶ Ascertain final enrollment target (up to 600)

SYN-004

Clinical trial development: Phase 3

Objectives:

̶ Prevention of CDAD and AAD among hospitalized patients receiving IV ceftriaxone and other beta-lactam antibiotics ̶ Global study; multiple indications for IV beta-lactam therapy ̶ Demonstrate no effect on blood levels of antibiotic or primary diagnosis cure rates ̶ Relationship between measurable post-antibiotic dysbiosis and

• C. diff & other healthcare-related outcomes and

pharmacoeconomics

Antimicrobial stewardship

Trends in antibiotic prescribing & CDI England

10000 20000 30000 40000 50000 60000 1,000,000 2,000,000 3,000,000 4,000,000 5,000,000 6,000,000 7,000,000 2004 2005 2006 2007 2008 2009 2010 2011 Cephalosporin doses Fluoroquinolone doses CDI in > 65 y.o.

Year Defined daily doses Number of CDI cases in >65 yo

Ashiru-Oredope et al. J Antimicrob Chemother 2012; 67 Suppl 1: i51–i63 Wilcox MH et al. Clinical Infectious Diseases 2012;55(8):1056–63 http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1179745282388

• Prioritization & restriction led to high homogeneity

– Facilitated colonization by Enterobacteriaceae and non-fermentative Gram-negative bacilli – Outbreaks of carbapenem-resistant Acinetobacter spp. during carbapenem prioritization – ESBL-producing Enterobacteriaceae during cephalosporin prioritization

• Patterns favoring balanced use of different

antimicrobials should be preferred

• Antibiotic strategies promoting diversity may improve

the use of healthcare resources

Sandiumenge A, et al. J Antimicrob Chemother. 2006;57:1197-1204. Sandiumenge A, et al. Chest. 2011;140:643-651.

Low diversity antibiotic prescribing

Paradigm Shift

Fewer CDIs expected with co-administration of SYN-004

SYN-004 Paradigm

SYN-004 + β-lactam Antibiotics*

SYN-004 designed to protect the natural balance

• f the gut microbiome during antibiotic use

PREVENTION

* Intended to include penicillins plus cephalosporins

Microbiome Analyst & Investor Meeting New York City

• C. difficile

SYN-004 Animated Video

Microbiome Analyst & Investor Meeting New York City

• C. difficile

Q&A Session

June 3, 2015

SYN – Microbiome Ana & Inv Meeting (6.3.2015)-FINAL

NYSE MKT: SYN Microbiome Analyst & Investor Meeting New York City