NYSE MKT: SYN. Protecting the Gut Microbiome

Transcription

1 NYSE MKT: SYN Protecting te Gut Microbiome Microbiome R&D and Business Collaboration Forum: USA Josep Sliman, MD, MPH, Sr. Vice President, Clinical & Regulatory Affairs September 10, 2015

2 Forward-Looking Statements Tis presentation includes forward-looking statements on Syntetic Biologics current expectations and projections about future events. In some cases forward-looking statements can be identified by terminology suc as "may," "sould," "potential," "continue," "expects," "anticipates," "intends," "plans," "believes, "estimates, indicates, and similar expressions. Tese statements are based upon current beliefs, expectations and assumptions and are subject to a number of risks and uncertainties, many of wic are difficult to predict and include statements regarding our clinical trials, our establisment of collaborations and our execution of our growt strategy. Te forward-looking statements are subject to risks and uncertainties tat could cause actual results to differ materially from tose set fort or implied by any forward-looking statements. Important factors tat could cause actual results to differ materially from tose reflected in Syntetic Biologics forward-looking statements include, among oters, a failure of our product candidates to be demonstrably safe and effective, a failure to initiate clinical trials and if initiated, a failure to acieve te desired results, a failure to obtain regulatory approval for our product candidates or to comply wit ongoing regulatory requirements, regulatory limitations relating to our ability to promote or commercialize our product candidates for te specific indications, a lack of acceptance of our product candidates in te marketplace, a failure of us to become or remain profitable, a failure to establis collaborations, our inability to obtain or maintain te capital or grants necessary to fund our researc and development activities, a loss of any of our key scientists or management personnel, and oter factors described in Syntetic Biologics annual report on Form 10-K for te year ended December 31, 2014, subsequent quarterly reports on Form 10-Qs and any oter filings we make wit te SEC. Te information in tis presentation is provided only as of te date presented, and Syntetic Biologics undertakes no obligation to update any forward-looking statements contained in tis presentation on account of new information, future events, or oterwise, except as required by law. 2

3 Human Microbiome Te body as 10 times as many microbe cells as uman cells Human Microbiome > 1,000,000 Genes Human Genome 23,000 Genes 99% of Genes in te body are Microbial, NOT Human Leveraging te microbiome could significantly cange medicine Source: ttp://commonfund.ni.gov/mp/overview.aspx 3

4 Diseases Directly Influenced by te Gut Microbiome Source: Genome Medicine 2011, 3:14 ttp://genomemedicine.com/content/3/3/14 4

5 Human Microbiome Over Time Response to Environmental Conditions and Life Stages Source: US National Library of Medicine. Image source: Ottman N, et al. (2012) Te function of our microbiota: wo is out tere and wat do tey do? Front. Cell. Inf. Microbio. 2:104. 5

6 Microbiome Product Pipeline Terapeutic Area C. difficile infection/ Antibiotic-associated diarrea (AAD) Irritable bowel syndrome wit constipation (IBS-C) Product Candidate SYN-004 SYN-010 C Discovery Preclinical Pase 1 Pase 2 Pase 3 C - Cedars-Sinai Medical Center collaboration Completed Planned

7 Collateral Damage Caused by Antibiotic Use Imbalance of te gut microbiome Antibiotics Prevent/treat primary infections Carried to liver, transported to bile and excreted via large intestine May unintentionally upset natural balance of gut microbiome by killing off good bacteria A microbial imbalance in te gut microbiome provides an opportunity for overgrowt of armful patogenic organisms (e.g., C. difficile) wic may cause severe diarrea, damage to te colon and in some cases deat 24 million patients are administered IV antibiotics annually in te U.S. 1 1 Tis information is an estimate derived from te use of information under license from te following IMS Healt Incorporated information service: CDM Hospital database for full year IMS expressly reserves all rigts, including rigts of copying, distribution and republication. 7

8 C. difficile Infections (CDI) Preventing C. difficile is now a national priority National Action Plan to combat antibiotic resistance issued by Wite House in Marc 15 1 CDI is currently te most prevalent ospital-acquired infection in te U.S., according to te CDC Surpassed meticillin-resistant Stapylococcus aureus (MRSA) CDI as been identified as an urgent public ealt treat by te CDC, FDA and EU ealt autorities CDI in te U.S.: 1.1 million patients infected wit C. difficile annually 2 Patients wit C. difficile ospitalized approximately 4-7 extra days 3 $8.2 billion in costs associated wit C. difficile-related stays in ospital 4 Up to ~25% of CDI patients ave a recurrence witin 1-3 monts 5-7 >30,000 C. difficile-related deats annually 8 1 ttps:// 2 Tis information is an estimate derived from te use of information under license from te following IMS Healt Incorporated information service: CDM Hospital database for full year IMS expressly reserves all rigts, including rigts of copying, distribution and republication. 3 (APIC) National Prevalence Study of Clostridium difficile in U.S. Healtcare Facilities. November 11, Agency for Healtcare Researc and Quality. Healtcare and Cost Utilization Project. Statistical Brief #124. Clostridium difficile Infections (CDI) in Hospital Stays, January Louie TJ, et al. N Engl J Med 2011;364: Cornely OA, et al. Lancet Infect Dis 2012;12: Vardakas KZ, et al. Int J Antimicrob Agents 2012;40: U.S. Department of Healt & Human Services. Agency for Healtcare Researc and Quality. January 25, 2012.

9 Paradigm Sift Fewer CDIs expected wit co-administration of SYN-004 Current Paradigm Antibiotics β-lactam Fluoroquinolone Clindamycin Oter C. difficile Infections (CDI) Treatments Metronidazole Vancomycin Fidaxomicin SYN-004 Paradigm SYN β-lactam Antibiotics* PREVENTION SYN-004 designed to protect te natural balance of te gut microbiome during antibiotic use * Intended to include penicillins plus cepalosporins 9

10 First Generation Candidate Validates Concept Proof of concept data demonstrated from Pase 1 and 2 studies Original tecnology developed by Finnis biotecnology company, Ipsat Terapies Oy First generation candidate, P1A, was evaluated in four Pase 1 and one Pase 2 clinical trials conducted in Europe In total, 112 patients and 143 ealty normal subjects participated in te studies Well tolerated wit no safety concerns identified Prevented te occurrence of AAD Preserved te normal intestinal microflora wen co-administered wit IV ampicillin or piperacillin Did not alter te PK profile of IV piperacillin or ampicillin nor te efficacy of ampicillin in patients wit respiratory infection requiring ospitalization 10

11 Second Generation Enzyme SYN-004 Activity against a broader spectrum of beta-lactam antibiotics SYN-004 represents next generation beta-lactamase enzyme Based on single amino acid cange Expected to ave activity against bot penicillins and certain cepalosporins Due to te structural similarities between P1A and SYN-004, IND leveraged certain preclinical data collected on P1A in support of an IND for SYN-004 Patents and pending patents Composition of matter claims and parmaceutical compositions of beta-lactamases, including SYN-004, was issued in November 2014 (U.S. Patent 8,894,994) Carries a term to at least 2031 An extensive portfolio of granted use patents and pending patent applications for SYN-004- related tecnology Additional patent filings covering composition of matter claims could extend patent protection of SYN-004 to

12 SYN-004 Co-Administered wit IV Antibiotics Designed to neutralize β-lactam antibiotics in GI tract 1. SYN-004 is an oral enzyme tablet (blue) to be co-administered wit IV antibiotics (yellow). 2. IV antibiotics can upset te natural balance of te gut microbiome, killing good bacteria, allowing for te overgrowt of C. difficile. SYN-004 Antibiotic 3. SYN-004 is intended to remain in te GI tract and neutralize IV antibiotics (black), protecting te natural balance of te gut microbiome. 4. Co-administration of SYN-004 is intended to allow te IV antibiotic (yellow) to treat te primary infection wile protecting te gut microbiome (blue), and preventing CDI. To view te SYN-004 mecanism of action video, please visit: ttp:// 12

13 SYN-004 Clinical trial development Completed Pase 1a (40 participants) and 1b (24 participants) trials PK data supports tat SYN-004 sould ave no effect on te IV antibiotic in te bloodstream No clinically significant safety events were observed; well tolerated by participants Initiated first Pase 2a trial (Marc 2015) Caracterize SYN-004 activity on ceftriaxone in te small intestine Demonstrate SYN-004 as no activity on ceftriaxone in te bloodstream SYN-004 degraded ceftriaxone in te cyme of initial four of 12 expected ealty participants wit functioning ileostomies witout affecting ceftriaxone in te bloodstream (July 2015) Initiated second Pase 2a trial (June 2015) Caracterize SYN-004 activity on ceftriaxone in te small intestine in te presence of esomeprazole, an approved, over-tecounter proton pump inibitor Pase 2b (Proof-of-Concept) trial objectives (initiation expected 3Q 2015) FDA Type C meeting requested (trial design and endpoints) Pase 3 trial vision Prevention of CDI and AAD among ospitalized patients receiving IV ceftriaxone and oter beta-lactam antibiotics Global study; multiple indications for IV beta-lactam terapy Demonstrate no effect on blood levels of antibiotic or primary diagnosis cure rates 13

14 SYN-004 Pase 2b trial design for CDI prevention ~75 Global Clinical Sites 370 patients 1:1 SYN Ceftriaxone Placebo + Ceftriaxone Primary Endpoint: Prevention of CDI Secondary Endpoints: Prevention of AAD Limiting disruption of gut microbiome diversity 14

15 SYN-004: Market Potential Intended to target certain IV β-lactam antibiotics ~118M doses of SYN-004 target antibiotics purcased by U.S. ospitals to fill patient prescriptions 1 ~27M prescriptions 2 SYN-004 Potential U.S. Market ~$13 Billion * ~14M patients 3 * Estimate based on te 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 Tis information is an estimate derived from te use of information under license from te following IMS Healt Incorporated information service: CDM Hospital database for full year IMS expressly reserves all rigts, including rigts of copying, distribution and republication. Based on U.S. market data in

16 C. difficile Market Overview 1 SYN-004 is a propylactic approac versus treatment Product Candidate SYN-004 * Dificid MK-3451A SER-109 ACAM- CDIFF Company Syntetic Merck Merck Seres Sanofi Compound Enzyme to protect microbiome Macrocyclic antibiotic Monoclonal antibody Microbiome terapeutic Vaccine Pase/Status Pase 2 Marketed Pase 3 Pase 2 Pase 2 Propylactic/ Primary prevention Treatment N/A Prevention of recurrence Route of administration N/A Oral Oral Infusion Oral *Based on preclinical & Pase 1 data and Company expectations N/A Injections (3X over 30 days) Currently te only metods for preventing primary C. difficile infection are troug antibiotic stewardsip and infection control 1 Not a compreensive list of pipeline products; representative of compounds tat are te fartest along in clinical development Sources: GlobalData; Corporate pipeline websites 16

17 Patogen-Specific Microbiome Terapeutic Treating te underlying cause not symptoms SYN APPROACH: Anti-Arcaea specific terapeutic 17

18 Irritable Bowel Syndrome IBS Prevalence IBS is a cronic GI disorder caracterized as a group of symptoms Diarrea/constipation Abdominal discomfort Bloating Severely impacts and reduces quality of life Statistics 10-15% of te global population Wo is affected? Women = 66.1%; Men = 33.9% IBS-D = 53%; IBS-M = 27%; IBS-C = 20% SYN focused on te treatment of IBS-C IBS Prevalence (age > 10)* US 17.2M EU5 16.5M Japan 7.0M Total 40.7M * Forecast uses stringent disease diagnosis criteria (ROME II) to ensure market relevance and a population most likely to receive a diagnosis and prescription drug treatment. Source: GlobalData Publication Irritable Bowel Syndrome Global Drug Forecast and Market Analysis

19 SYN-010: Modified-Release Lovastatin Designed to reduce metane production by M. smitii in te intestine Bacteroides tetaiotaomicron is one of many bacterium tat ferments carboydrates in te gut wic releases H 2 and CO 2 H 2 Carboydrates Metanobrevibacter smitii arcea consumes ydrogen gas from Bacteroides and produces metane, wic is lost from gut as gas Gas Source: ttp://commons.wikimedia.org/wiki/file:intestine_and_stomac_-_transparent_-_cut.png 19

20 Metane Production: Underlying Cause of IBS-C Intestinal metane production is an underlying cause of constipation Critical discovery by Mark Pimentel, MD, and collaborators at Cedars-Sinai Extensive clinical evidence in IBS-C and now cronic idiopatic constipation (CIC) Reduction of intestinal metane as been sown to reverse constipation and improve IBS-C symptoms Significant opportunity for a terapy for cronic use in IBS-C Treat te underlying cause of constipation Not just stool mass transit No diarrea Targeted to te intestine Minimized systemic drug levels Not antimicrobial Suitable for cronic use Minimal disruption of te microbiome 20

21 ΔCH min Normalized to Control Anti-Metanogenic Terapy for IBS-C Lovastatin demonstrated significant reduction in metane gas Studies demonstrated tat statins in animal feed reduced metane gas in ruminant animals (4-cambered stomac) Dr. Pimentel translated te use of statins to reduce metane in umans (single-camber stomac) by evaluating commercial lovastatin formulations in select IBS-C patients in is practice Dr. Pimentel furter demonstrated tat lovastatin is uniquely effective in reducing metane compared to oter statins In vitro metane production analysis wit uman IBS-C stool samples Control Lovastatin Statin 2 Statin 3 Statin 4 Statin 5 Source: Dr. Pimentel et al Cedars-Sinai Medical Center 21

22 M. smitii (cfu/g tissue) Total Bacteria (cfu/g tissue) Lovastatin: Targeting Production of Metane Gas Minimal impact on microbiome Effect of lovastatin on levels of M. smitii and total bacteria in rat GI tract after 10 days oral gavage dosing 3.5E E+06 Placebo Lovastatin (1.5 mg/rat) M. smitii Total bacteria 7.0E E+07 Placebo Lovastatin (1.5 mg/rat) 2.5E E E E E E E E E E E+00 Duodenum Jejunum Ileum Cecum Left Colon 0.0E+00 Duodenum Jejunum Ileum Cecum Left Colon Rat tissue Rat tissue Source: Morales, W. et al. (2015) Gastroenterology 148(4): S

23 SYN-010: Differentiators Proprietary, modified-release lovastatin Modified-release lovastatin formulation targeting intestinal metane production Leveraging detailed parmacokinetic and safety profiles from decades of prior clinical use Designed to treat te underlying cause of constipation Patents and pending patents licensed troug Cedars-Sinai An extensive portfolio of granted use patents and pending patent applications for SYN-010 Additional worldwide patent filings covering composition of matter claims could extend patent protection of SYN-010 to 2035 Anticipate 505(b)(2) development patway To view te SYN-010 mecanism of action video, please visit: ttp:// 23

24 SYN-010 for IBS-C Clinical development Preclinical data Lovastatin prevented proliferation of metanogens in rat ileum wit minimal impact on remaining microbiome Ex vivo clinical data Lovastatin prevented metane production by metanogens in uman stool Initiated first SYN-010 Pase 2 placebo-controlled, acute clinical trial (June 2015) Multiple sites in U.S. Second SYN-010 Pase 2 ig-dose extension clinical trial (initiation expected 2H 2015) Pursue SYN-010 Pase 3 clinical trials Estimated to begin in

25 SYN-010 Pase 2 trial design for IBS-C multiple sites in U.S 12 Weeks Study #1 4 Week Acute Treatment Topline Analysis Study #1 Study #2 8 Week Extension Treatment Topline Analysis Study #2 SYN-010 Hig Dose 20 patients 60 patients SYN-010 Low Dose 20 patients Placebo 20 patients SYN-010 Hig Dose 60 patients* *Eligible Study #1 completers rollover immediately into Study #2 Primary Endpoint: Reduction of breat metane Secondary Endpoints: Reduction in abdominal pain and bloating Increase in complete spontaneous bowel movement (CSBM) 25

26 IBS Market Overview 2015 IBS Global Terapeutic Sales Forecast ~$669.3M $30.3 $68.8 $61.4 $220.9 $146.0 $141.9 rifaximin lubiprostone linaclotide alosetron ramosetron oters Global IBS Sales in 2023 are expected to be greater tan $1.5B Market growt attributed to: Increased uptake of Linzess and label expansion of Xifaxan Launc of 4 late-stage pipeline products including 2 late-stage for IBS-C: Plecanatide - Synergy Tenapanor - Ardelyx Source: IMS Audited Sales Data, Midas Global Sales (Analytics Link) 26

27 IBS-C Market Overview 1 SYN-010 targets underlying cause versus competition Product Candidate SYN-010 * Linzess Amitiza OTC Laxatives Plecanatide Company Syntetic Ironwood Takeda Various Synergy Pase/Status Pase 2 Marketed Marketed Marketed Pase 3 Treat underlying cause of IBS-C Treat symptoms Relieves constipation Relieves pain Causes more regular bowel movements Does not cause severe diarrea *Based on preclinical data and Company expectations 1 Not a compreensive list of pipeline products; representative of compounds tat are te fartest along in clinical development Source: GlobalData; Corporate pipeline websites 27

28 Milestones: Acieved & Upcoming Terapeutic Area/ Product Candidate C. difficile/aad SYN-004: Pase 1a/1b Pase 2a (1 st ileostomy study; ceftriaxone) Pase 2a (2 nd ileostomy study; ceftriaxone+ppi) Pase 2b proof-of concept Pivotal Pase 3 trial(s) IBS-C SYN-010: Pase 2 (1 st study; acute, placebo-controlled) Pase 2 (2 nd study; extension, SYN-010 only) Pivotal Pase 3 trial(s) Timeline 1Q 2015 Positive topline Pase 1b results 1Q 2015 Positive Pase 1a/1b PK data 1Q 2015 Initiated Pase 2a 3Q 2015 Supportive Pase 2a data from initial 4 of 12 expected participants 3Q 2015 Report Pase 2a topline data 2Q 2015 Initiated Pase 2a 2H 2015 Report Pase 2a topline data 3Q 2015 Initiate Pase 2b trial 2H 2015 Interim analysis of blinded data 2016 Initiate Pase 3 trial(s) 1Q 2015 SYN-010 modified-release formulation of lovastatin 2Q 2015 Initiated Pase 2 2H 2015 Report Pase 2 topline data 2H 2015 Initiate Pase 2 1H 2016 Report Pase 2 topline data 2016 Initiate Pase 3 trial(s) 28

29 NYSE MKT: SYN Protecting te Gut Microbiome Microbiome R&D and Business Collaboration Forum: USA Josep Sliman, MD, MPH, Sr. Vice President, Clinical & Regulatory Affairs September 10, 2015 SYN Microbiome Forum USA Slides ( )-FINAL