Theriva Biologics, Inc. · AMEX:TOVX
Theriva Biologics — Synthetic Biologics — Biotech Showcase 2018
91 slides from Theriva Biologics's conference presentation, Jan 8, 2018
Slide 1: Biotech Showcase 2018
Biotech Showcase 2018 Steven Shallcross - Interim CEO & CFO January 9, 2018
Slide 2: Forward-Looking Statements
Forward - Looking Statements This presentation includes forward - looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 , as amended, on Synthetic Biologics’ current expectations and projections about future events . In some cases forward - looking statements
Slide 3: About Synthetic Biologics
About Synthetic Biologics (NYSE American: SYN) • Microbiome focused company pioneering proprietary late - stage product candidates designed to protect and preserve the gut microbiome: • SYN - 004 (ribaxamase), for the prevention of antibiotic - mediated primary C. difficile infection (CDI), pathogen
Slide 4: Our Leadership Team
Our Leadership Team 4 Steven Shallcross, Interim CEO & CFO Vanda Pharmaceuticals, Inc., Empire Petroleum Partners, LLC, Innocoll AG (formerly privately held Innocoll Holdings, Inc.) Joseph Sliman, MD, MPH, CMO Vanda Pharmaceuticals, Inc., MedImmune , Inc., DynPort Vaccine Raymond Stapleton, PhD, SVP
Slide 5: Building a Deep Pipeline Focused on the Microbiome
Building a Deep Pipeline Focused on the Microbiome Therapeutic Area Product Candidate Preclinical Phase 1 Phase 2 Phase 3 Prevention of CDI and AMR [co-administer with IV ?-lactam] ribaxamase Oral ?-lactamase SYN-004 Prevention of CDI and AMR [co-administer with IV Carbapenem] Oral carbapenemase SYN
Slide 6: The Gut Microbiome: A Community of Microbes
The Gut Microbiome: A Community of Microbes • Immune system • Metabolism • Obesity • Inflammatory diseases • Central nervous system disorders Imbalance in the microbiome has been linked to multiple health issues 1,2,3 gut bacterial species have now been characterized 5 > 1,000 ~ 100 trillion microbi
Slide 7: SYN-004 (ribaxamase)
SYN-004 (ribaxamase) Synthetic (6)
Slide 8: Antibiotics Disrupt the Balance of Bacteria in the Gut Microbiome
Antibiotics Disrupt the Balance of Bacteria in the Gut Microbiome A healthy microbiome protects the body from infection Antibiotics wipe out good and bad bacteria Resistant bacteria (bad bacteria) multiply and take over Body primed for infection resistant bacteria spreads Image Credit: CDC 7 Leaving
Slide 9: CDI: An Urgent Threat in the U.S. and Growing Global Concern
9. Lessa, F.C., Winsto., & McDonald, L.C; (2015). Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. New England Journal of Medicine. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMc1505190#t=article (Last accessed Aug
Slide 10: Antimicrobial Resistance: Public Policy Tailwind
Antimicrobial Resistance: Public Policy Tailwind • AMR is a serious threat — world leaders are taking action • Government recognizes need to expedite drug review timelines • Leaders in industry and academia developing action plans • Synthetic Biologics is pioneering microbiome science to prevent the
Slide 11: Worldwide Market Opportunity
Worldwide Market Opportunity All Antibiotics 77.3B Doses IV Penicillins and Cephalosporins 7.5B Doses Source: IMS Health 2017 – doses in standard units Carbapenems, Penicillins and Cephalosporins 49.6 Doses Our product pipeline covers 64 % of the World’s antibiotics and 57 % of the United States’ an
Slide 12: Ribaxamase Impact Could be Broad-Reaching
Gut Dysbiosis Seeking to transform anti - infective standard - of - care Ribaxamase Impact Could be Broad - Reaching Infection e.g. LRTI β - Lactam Antibiotic AbX = antibiotic. AMR = antimicrobial resistance. CDI = C. difficile infection, defined as diarrhea wherein the stool sample is positive for
Slide 13: SYN-004 (ribaxamase): Proprietary oral formulation of a class A β-lactamase enzyme
N S NH 2 N O CH 3 O NH NH S O S N N NH O O CH 3 NaO O OH N S NH 2 N O CH 3 O NH N S O S O N N NH O O CH 3 NaO SYN - 004 (ribaxamase) Proprietary oral formulation of a class A β - lactamase enzyme • Proprietary, enteric - protected, oral formulation of a class A, β - lactamase enzyme (P3A) • First ge
Slide 14: What is ribaxamase?
• Two proprietary oral 75mg capsules (custom designed oral β - lactamase) • Designed to protect the natural balance of microbes in the gut microbiome during antibiotic use • Did not interfere with the efficacy of IV antibiotics in Phase 2 studies SYN - 004 (ribaxamase) 14 • be co - administered with
Slide 15: Ribaxamase Phase 2b Clinical Trial Design
Prevention of CDI in patients receiving IV ceftriaxone to treat a LRTI 1 Ribaxamase Phase 2b Clinical Trial Design (N=412) ¹ LRTI = clinical diagnosis of moderate to severe lower respiratory tract infection. ²Ceftriaxone in - patient IV dosing regimen and length of dosing were determined by local st
Slide 16: Ribaxamase Phase 2b Topline Results
Data consistent with MoA of protecting gut microbiome from antibiotic - mediated disruption Ribaxamase Phase 2b Topline Results 16 7 8 6 2 2 0 0 1 2 3 4 5 6 7 8 9 Local Lab Central Lab Patients Treated for CDI Placebo Ribaxamase P=0.045 P=0.027 P=0.007 69 71 36 40 0 10 20 30 40 50 60 70 80 VRE @ 72
Slide 17: Ribaxamase reduced CDI incidence
• Ribaxamase caused a 71.4% reduction in the incidence of CDI in patients treated with IV ceftriaxone • No subjects in SYN - 004 group required subsequent treatment for CDI • Ribaxamase caused a 43.9% reduction in new colonization by VRE • Prevention of antibiotic mediated dysbiosis is expected to p
Slide 18: Ribaxamase Development Plan
• Gain clarity from the FDA on the clinical development path forward for SYN - 004 • End of Phase 2 meeting anticipated H2 2018 • Ongoing interactions with the Centers for Disease Control and Prevention on potential clinical research and post - study programs • Evaluating additional government suppo
Slide 19: Our Strategic and Commercial Priorities
Our Strategic and Commercial Priorities Commercialization 19 Expect to build and expand our platform of preventative products • SYN - 004 (ribaxamase) - Phase 3 ready • SYN - 006 - oral carbapenemase (pre - clinical) • SYN - 007 - oral formulation of ribaxamase for co - administration with oral β -
Slide 20: Ribaxamase Patent Position
Pending Patent Applications • Methods of Manufacture • Clinical Dosing, Formulation • Methods of Treatment Expires 2035/6 Patented other β - Lactamase Composition of Matter & Uses Expires 2035 Patented ribaxamase Composition of Matter Expires 2031 Extensive patent portfolio, multiple protection stra
Slide 21: SYN-010
SYN - 010
Slide 22: Irritable Bowel Syndrome (IBS)
• There are multiple IBS subtypes characterized by stool consistency and bowel movement frequency • Constipation (IBS - C) , diarrhea (D), mixed (M), unsubtyped (U) • Functional gastrointestinal disorder ( FGID ) characterized by abdominal pain associated with abnormal bowel movements • IBS is the m
Slide 23: Constipation Remains a Large Unmet Medical Need
Up to 1 in 7 (14%) US adults has chronic constipation¹ $3,508 average additional healthcare cost per patient per year² Up to 1 in 20 (5%) US adults suffers from IBS - C³ $3,856 average additional healthcare cost per patient per year ³ Only 8% of IBS patients and 14% of CIC patients are completely sa
Slide 24: IBS and Constipation Markets are Growing
IBS and Constipation Markets are Growing More than 2x growth in 4 years! US IBS and Constipation Market 1 • Digital and DTC campaigns are enhancing awareness of both IBS and gut health • New entrants are growing the market , not cannibalizing it 1 • Only 26% of patients are “very satisfied” with cur
Slide 25: SYN-010: Competitive Overview
SYN - 010: Competitive Overview Product Candidate SYN - 010 Linzess Amitiza Trulance Tenapanor OTC Laxatives Company Synthetic Allergan Takeda Synergy Ardelyx Various Phase/Status Planned pivotal 2b/3 Marketed Marketed Marketed Phase 3 Marketed Designed to treat underlying cause of IBS - C Designed
Slide 26: SYN-010 is a Unique Approach to Treating IBS-C
Directly targeting a microbial cause of IBS - C symptoms SYN - 010 is a Unique Approach to Treating IBS - C Bisacodyl Erythromycin Prucalopride Senna Linaclotide Lubiprostone Plecanatide Tenapanor Miralax Senna Target a Cause Hydrate the Stool Stimulate intestinal motility Stimulate intestinal water
Slide 27: How Does SYN-010 Work?
How Does SYN - 010 Work? • Methane produced by M. smithii has been shown to cause constipation, pain and bloating 1 • Modified - release formulation of lovastatin lactone optimal for reducing methane - production by certain gut microorganisms ( M. smithii ) • SYN - 010 acts in the intestinal lumen t
Slide 28: SYN-010 Phase 2a Clinical Study Design
SYN - 010 Phase 2a Clinical Study Design Multicenter, randomized, controlled, double - blinded, 4 - week trial ( RCT ) followed by an 8 - week open - label extension ( EXT ) | | | | | | | | | | | | | | Screen 1 7 14 21 28 35 42 49 56 63 70 77 84 Day CH 4 >10 ppm Randomized (RCT)¹ Open - Label Extens
Slide 29: Delivering Clinical Outcomes: SYN-010 Phase 2
• CSBM’s improved in all three SYN - 010 groups over placebo • No serious adverse events and very few treatment emergent adverse events reported in clinical trials 18% 14% 0% 32% 45% 18% 5% 23% 21% 37% 11% 42% 56% 63% 39% 73% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% CSBM* PAIN OVERALL (FDA) BLOAT
Slide 30: SYN-010 Clinical Development Status
• FDA recommended a first Phase 2b/3 adaptive clinical trial • N=840 (280/arm) • Multicenter, randomized, double - blind, placebo - controlled study • Single daily doses of Placebo, SYN - 010 (21 mg) or SYN - 010 (42 mg) for 12 weeks • Both low and high - breath methane patients to be included • FDA
Slide 31: SYN-010 Patent Position
Pending Patent Applications • Formulations • Methods of Use in Specific Patient Populations • Clinical Dosing Expires 2035 Patented and Pending Methods of Treatment Treat Constipation with SYN - 010 in Screened Patients Expires 2034 Patented Methods of Treatment Broadest Indication Expires 2023 Exte
Slide 32: Preclinical Pipeline
Preclinical Pipeline
Slide 33: SYN-005: Treatment and Prevention of Pertussis
SYN - 005: For the Treatment and Prevention of Pertussis Despite vaccination, pertussis remains a US and global health problem 33 • Worldwide – 16 million cases & 195,000 deaths in 2015 (21,000 cases in the U.S.) 1,2 • Pertussis remains an unmet medical need, especially in the developing world • SYN
Slide 34: SYN-020: Intestinal Alkaline Phosphatase (IAP)
• Naturally - occurring intestinal enzyme that maintains gut health via multiple mechanisms • Detoxifies inflammatory mediators (e.g. endotoxin) • Tightens the gut barrier • Regulates luminal pH and fat absorption • Published studies demonstrated efficacy in humans and multiple animal models • Oppor
Slide 35: Investment Highlights
Investment Highlights
Slide 36: Focus on Two Key Objectives as we Build Capabilities
Focus on Two Key Objectives as we Build Capabilities Financial Stewardship Clinical/ Regulatory and Med Affairs Manufacturing Innovation R&D Capabilities Marketing and Commercial Key Objectives: 1. Gain clarity from the FDA on the clinical development path forward for SYN - 004 (ribaxamase) • Ongoin
Slide 37: Why Synthetic Biologics? Why Now?
Why Synthetic Biologics? Why Now? • Microbiome focused company pioneering proprietary late - stage product candidates designed to protect and preserve the gut microbiome: • SYN - 004 (ribaxamase), for the prevention of antibiotic - mediated primary C. difficile infection (CDI), pathogenic overgrowth
Slide 38: Thank You
Thank You
Slide 39: Appendix
Section Title APPENDIX
Slide 40: Preventing CDI and AMR: SYN-004 (ribaxamase)
Preventing CDI and AMR SYN - 004 (ribaxamase): Protecting the Microbiome from Antibiotic Damage
Slide 41: Ribaxamase is Designed to Prevent Dysbiosis
β - lactam antibiotic excreted into the GI tract can cause dysbiosis Ribaxamase is Designed to Prevent Dysbiosis Antibiotic Excreted in Bile ANTIBIOTIC EFFECTS Disrupted microbiome Proliferation of pathogens such as C. difficile Emergence of antimicrobial resistant species (AMR) Systemic (IV)
Slide 42: Ribaxamase is Designed to Prevent Dysbiosis
Degrading excess β - lactam antibiotic excreted into the GI tract Ribaxamase is Designed to Prevent Dysbiosis SYN - 004 (ribaxamase) Antibiotic Excreted in Bile Systemic (IV) β - lactam antibiotic Treat Primary Infection (e.g. pneumonia) Stomach Duodenum Jejunum Ileum Cecum Colon 42 Enteric protecti
Slide 43: SYN-004 Phase 2a: Ceftriaxone degradation in chyme
2 Degradation of ceftriaxone in chyme from healthy adults with an ileostomy SYN - 004 (ribaxamase) Phase 2a Clinical Trials ¹ CRO = Ceftriaxone 1 g administered as a 30 min IV infusion; SYN = SYN - 004 administered orally as 75 mg capsules. ² PPI = esomeprazole 40 mg q.d. taken each morning for 5 -
Slide 44: Both SYN-004 doses effectively degraded ceftriaxone in chyme
Both SYN - 004 75 mg and 150 mg effectively degraded ceftriaxone in chyme SYN - 004 (ribaxamase) Phase 2a Clinical Trials ¹ Kokai - Kun JF et al. (2017) Antimicrob Agents Chemother 61: e02197 - 16. CRO = Ceftriaxone 1 g administered as a 30 min IV infusion; SYN = SYN - 004 75 mg or 150 mg administer
Slide 45: Esomeprazole did not alter SYN-004 ability to degrade ceftriaxone
• Slightly earlier SYN - 004 release with esomeprazole • Ceftriaxone still completely degraded in chyme Esomeprazole did not alter SYN - 004 ability to degrade ceftriaxone in chyme SYN - 004 (ribaxamase) Phase 2a Clinical Trials ¹ Kokai - Kun JF et al. (2017) Antimicrob Agents Chemother 61: e02197 -
Slide 46: Oral SYN-004 did not alter IV ceftriaxone plasma pharmacokinetics
Oral SYN - 004 ( ± esomeprazole) did not alter IV ceftriaxone plasma pharmacokinetics SYN - 004 (ribaxamase) Phase 2a Clinical Trials ¹ Kokai - Kun JF et al. (2017) Antimicrob Agents Chemother 61: e02197 - 16. CRO = Ceftriaxone 1 g administered as a 30 min IV infusion; SYN = SYN - 004 75 mg or 150 m
Slide 47: SYN-004 Phase 2a study demographics and safety
Parameter Study 1 Study 2 Dose Ceftriaxone (30 min IV infusion) 1.0 g 1.0 g 1.0 g SYN - 004 (oral - 0.5 h and +5.5 h) 75 mg 150 mg 150 mg Esomeprazole (oral, steady state) -- -- 40 mg Demographics¹ Subjects, n (% Female) 6 (16.7%) 5 (40.0%) 15 (26.7%) White / Other, % 83.3% / 16.7% 100% / -- 93.3% /
Slide 48: Ribaxamase Phase 2b Clinical Trial Design
Prevention of CDI in patients receiving IV ceftriaxone to treat a LRTI 1 Ribaxamase Phase 2b Clinical Trial Design (N=412) ¹ LRTI = clinical diagnosis of moderate to severe lower respiratory tract infection. ²Ceftriaxone in - patient IV dosing regimen and length of dosing were determined by local st
Slide 49: Ribaxamase caused a 71.4% reduction in CDI
Ribaxamase caused a 71.4% reduction in CDI 1,2 (achieved primary endpoint) Ribaxamase Phase 2b Clinical Trial Results ¹Patients are determined to have CDI (also called C. difficile associated diarrhea or CDAD) if they have diarrhea and the stool sample is positive for C. difficile toxin A and/or B (
Slide 50: Ribaxamase caused a 43.9% reduction in new colonization by VRE
Ribaxamase caused a 43.9% reduction in new colonization by VRE 1 Ribaxamase Phase 2b Clinical Trial Results ¹ VRE = Vancomyin - resistant enterococci; new colonization means patient samples were negative at screening but positive between day 1 and the indicated timepoint. ²New C. difficile colonizat
Slide 51: Trend to decreased diarrhea in ribaxamase groups
Trend to decreased diarrhea overall in ribaxamase treatment groups SYN - 004 (ribaxamase) Phase 2b Trial Results ¹ CDI (also called C. difficile associated diarrhea or CDAD) means the diarrhea stool sample is positive for C. difficile toxin A and/or B (or their respective genes, tcdA and/or tcdB );
Slide 52: Ribaxamase Phase 2b results summary
• Ribaxamase caused a 71.4% reduction in the incidence of CDI in patients treated with IV ceftriaxone • No subjects in SYN - 004 group required subsequent treatment for CDI ‒ All cases of CDI were due to new colonization by C. difficile • Subjects in the ribaxamase treatment group reported less diar
Slide 53: Antibiotic Effects on the Gut Microbiome
• Antibiotics disrupt the balance of commensal microbial species and enable the overgrowth of opportunistic pathogens • Disruption of the natural balance of the microbiome (termed dysbiosis ) is multifactorial, but antibiotics have the most profound effect • Antibiotic - mediated alterations to the
Slide 54: Ribaxamase Protection of the Microbiome
Measuring eradication, overgrowth, diversity and recovery Ribaxamase Protection of the Microbiome ¹Ceftriaxone in - patient IV dosing regimen and length of dosing were determined by local standard - of - care ²16S sequencing conducted by DNA Genotek Treatment Period 1 Follow - up 2 Screen Day 1 5 -
Slide 55: Ribaxamase Protected Microbial Diversity
Prevented Ceftriaxone(CRO) - mediated loss of α - diversity and enhanced microbiome recovery Ribaxamase Protected Microbial Diversity Note: Shannon Index and Chao1 represent α - diversity, a measure of the microbial community composition within a sample Size of each ball is relative to the standard
Slide 56: Ribaxamase Protected the Gut Microbiome from Antibiotic Changes
Ribaxamase Protected the Gut Microbiome 1 from Antibiotic Changes Placebo Ribaxamase T0 T1 Loss of Gut Microbes Overgrowth of Gut Microbes T0 T1 Prevents Loss of Gut Microbes Prevents Overgrowth of Gut Microbes ¹Data are a representative subset of all patients in each treatment group ²Each square re
Slide 57: Ribaxamase Attenuated Changes in Antibiotic Resistance Genes
Ribaxamase Attenuated Changes in Antibiotic Resistance Genes Placebo Ribaxamase Decreased Increased Vancomycin resistance genes β - lactamase genes Tet and erm resistance genes LefSe Analysis 57 Collection point T0 to T1, Placebo vs. Ribaxamase - treated patients
Slide 58: Resistome Analysis of Longitudinal Fecal Samples
Resistome Analysis of Longitudinal Fecal Samples • DNA extracted from 350 fecal samples sequenced by whole genome shotgun sequencing (Diversigen, Houston, TX) • Interrogated against the CARD database • 21,000,000 DNA matches • 1300 AMR genes identified with ~60,000 matches per sample • Including man
Slide 59: Ribaxamase Microbiome Conclusions
• Ribaxamase treatment significantly reduced loss of microbial diversity caused by ceftriaxone • Difference in loss of both α - and β - diversity for ribaxamase vs Placebo of p<0.01 at T1 and T2 • Ribaxamase treated patients had restoration of microbial diversity shortly after ceftriaxone was remove
Slide 60: Phase 2b demographics and adverse events
Parameter Placebo Ribaxamase Dose Ceftriaxone IV infusion, days 8.4 ± 2.9 8.5 ± 3.1 Ceftriaxone, total g received 17.7 ± 6.9 18.9 ± 9.1 Study drug exposure, days 11.0 ± 3.3 11.0 ± 3.5 Demographics¹ Subjects, n (% Female) 206 (38.8%) 206 (35.4%) White/Caucasian, n (%) 205 (99.5%) 206 (100%) Age , yea
Slide 61: SYN-004 Phase 2b Adverse Events
• Percentage of subjects reporting at least one treatment emergent adverse event ( TEAE ) was similar between SYN - 004 and Placebo treatment groups (40.8% vs 44.2%)¹ • Percentage of serious adverse events ( SAEs ) was higher in the SYN - 004 treatment group than the Placebo group (16.0% vs 10.2%) •
Slide 62: Expert Independent Third-Party Safety Review
Expert Independent Third - Party Safety Review Difference in cardiac fatal AEs attributable to disparity in underlying health, comorbidities “…the review of the medical history of all the subjects included in the study reveals significant imbalances between the study groups, regarding the prevalence
Slide 63: Disparity in Cardiac Fatal AEs Reflects Underlying Comorbidities
COPD 16 with Cor Pulmonale COPD 8 with Cor Pulmonale BUN⁴ Glucose³ 10 23 [4] 21 17 20 15 14 [1] 18 59 53 [1] 15 17 23 17 516 - 007 Cardiac Placebo [1]¹ SYN - 004 [6]² Disparity in Cardiac Fatal AEs Reflects Underlying Comorbidities 63 ¹Data are no. Patients [no. fatal AEs]. ²One patient with cardiac
Slide 64: Safety review conclusions
Following an extensive review, Synthetic Biologics and its independent consultants and advisors have concluded that: • The increased number of cardiac fatal AEs in the SYN - 004 treatment group was attributable to a random disparate distribution of cardiac risk factors that predisposed patients in t
Slide 65: Ribaxamase Expansion Programs
• SYN - 007: new oral formulation of ribaxamase for co - administration with oral β - lactam antibiotic(s) • Promising preclinical studies of SYN - 007 co - administered with oral amoxicillin¹ ‒ Key challenge to ensure SYN - 007 does not alter oral antibiotic absorption, PK and systemic therapeutic
Slide 66: Ribaxamase Patent Position
Pending Patent Applications • Methods of Manufacture • Clinical Dosing, Formulation • Methods of Treatment Expires 2035/6 Patented other β - Lactamase Composition of Matter & Uses Expires 2035 Patented ribaxamase Composition of Matter Expires 2031 Extensive patent portfolio, multiple protection stra
Slide 67: SYN-010: Targeting a Microbial Cause of Symptoms in IBS-C
SYN - 010: Targeting a Microbial Cause of Symptoms in Irritable Bowel Syndrome with Constipation (IBS - C)
Slide 68: SYN-010 is a Unique Approach to Treating IBS-C
Directly targeting a microbial cause of IBS - C symptoms SYN - 010 is a Unique Approach to Treating IBS - C Bisacodyl Erythromycin Prucalopride Senna Linaclotide Lubiprostone Plecanatide Tenapanor Miralax Senna Target a Cause Hydrate the Stool Stimulate intestinal motility Stimulate intestinal water
Slide 69: Intestinal Methane Production
• Methane production ( methanogenesis ) is ubiquitous in the human intestine • Disposes of hydrogen formed during carbohydrate digestion by bacteria¹ - ³ • Methane production in the human intestine is almost entirely due to the microbe Methanobrevibacter smithii • M. smithii resides predominantly in
Slide 70: Reducing Intestinal Methane Production
• Methane inhibition is distinct from cholesterol lowering • Lovastatin systemic absorption is not required to treat IBS - C • Archaeal cell membrane synthesis requires HMG - CoA reductase (HMGR), an enzyme integral to cholesterol synthesis in humans • Can statins act as methane inhibitors? • Lovast
Slide 71: Proposed Lovastatin Lactone Antimethanogenic MOA
Proposed Lovastatin Lactone Antimethanogenic MOA ¹Gottlieb K et al. (2015) Aliment Pharmacol Ther 43 :197 - 212. ²Muskal S et al. (2016) F1000Research 5 :606. Lovastatin lactone binds more effectively to F 420 - dependent methylenetetrahydromethanopterin dehydrogenase 1 (mtd) than does the native co
Slide 72: SYN-010 Modified Release Lovastatin Lactone
Proactively targeting a cause of constipation, pain and bloating in IBS - C SYN - 010 Modified Release Lovastatin Lactone SYN - 010 ¹Hubert S et al. (2017) J Pharm Sci in press http://dx.doi.org/10.1016/j.xphs.2017.09.028. ²Morales W et al. (2015) Gastroenterology 148 (Suppl 1) : S - 779 - 80. Stoma
Slide 73: SYN-010 Pharmacokinetics in Healthy Volunteers
Reduced β - hydroxyacid levels compared to equivalent doses of marketed formulations² Confirmed the proposed release profile (single dose, n=8) SYN - 010 Pharmacokinetics in Healthy Volunteers Dose (n) C max (ng/mL) AUC 0 - 24 (ng.h/mL) Lactone Acid Lactone Acid SYN - 010 21 mg (8) 1.7 ± 1.4 1.2 ± 0
Slide 74: SYN-010 plasma pharmacokinetic profile after daily doses
SYN - 010 plasma pharmacokinetic profile after single daily doses x 4 days (n =8) SYN - 010 Pharmacokinetics in Healthy Volunteers ¹Data are mean ± SD (n=8); plasma concentrations are from samples collected from fasted healthy volunteers administered a single, oral dose of SY N - 010 21 mg, 42 mg or
Slide 75: SYN-010 Doses Over 42 mg are Not Needed for IBS-C
SYN - 010 Doses Over 42 mg are Not Needed for IBS - C Trend to altered serum lipid profiles with SYN - 010 84 mg dose 1 • Stool concentrations suggest that doses of SYN - 010 less than 21 mg may not deliver effective methane - inhibiting lovastatin lactone levels to the colon • Doses above 42 mg are
Slide 76: SYN-010 Phase 2a Clinical Study Design
SYN - 010 Phase 2a Clinical Study Design Multicenter, randomized, controlled, double - blinded, 4 - week trial ( RCT ) followed by an 8 - week open - label extension ( EXT ) | | | | | | | | | | | | | | Screen 1 7 14 21 28 35 42 49 56 63 70 77 84 Day CH 4 >10 ppm Randomized (RCT)¹ Open - Label Extens
Slide 77: CSBM Monthly Response
• Greatest response in Cohort 2 (lowest baseline CSBMs) CSBM Monthly Response ¹Complete Spontaneous Bowel Movements ( CSBMs ; if any) were reported by subjects each day in an electronic diary. ²Nominal P values (Chi - square) reported for RCT are for SYN - 010 vs Placebo and for EXT are for within -
Slide 78: Abdominal Pain Monthly Response
• Response increased on transition to higher dose and increased / persisted with longer dosing Abdominal Pain Monthly Response Pain Monthly Response A ≥30% decrease from day 1 baseline in weekly average worst abdominal pain score in at least 50% of weeks in the month 1,2 ¹Abdominal pain score is the
Slide 79: Bloating Monthly Response
• Response increased on transition to higher dose and increased / persisted with longer dosing • Bloating has been reported as the most bothersome symptom by IBS - C patients in international studies³ , ⁴ Bloating Monthly Response Bloating Monthly Response A ≥30% decrease from day 1 baseline in week
Slide 80: Overall Monthly Response
• Response increased on transition to higher dose and increased / persisted with longer dosing Overall Monthly Response Overall Monthly Response A CSBM Response and an Abdominal Pain Response in the same week for at least 50% of the weeks in the month ¹Nominal P values (Chi - square) reported for RC
Slide 81: Phase 2a baseline demographics and symptoms
Parameter Cohort 1 Cohort 2 Cohort 3 Study¹ RCT | EXT RCT | EXT RCT | EXT SYN - 010 dose Placebo | 42 mg _ 21 mg | 42 mg 42 mg | 42 mg Dosing period, weeks 1 - 4 | 5 - 12 1 - 4 | 5 - 12 1 - 4 | 5 - 12 Baseline Demographics (day 1)² No. Subjects (Female %) 22 (77.3%) 22 (86.4%) 19 (73.7%) White / Bla
Slide 82: Phase 2a adverse events
Parameter Cohort 1 Cohort 2 Cohort 3 Study RCT EXT RCT EXT RCT EXT SYN - 010 Dose Placebo 42 mg 21 mg 42 mg 42 mg 42 mg Enrolled , n 22 17 22 20 19 17 Withdrew, n 2 2 2 2 2 1 Reported SAE, n 0 0 0 0 0 0 Reported TEAE, n 1 2 2 2 2 2 Treatment Emergent Adverse Event (TEAE; Relationship to Treatment)¹
Slide 83: SYN-010: No Meaningful or Persistent Systemic Effects
SYN - 010 No Meaningful or Persistent Systemic Effects Consistent with reduced systemic exposure to lovastatin β - hydroxyacid • Plasma trough levels of lovastatin species measured during the RCT were low and variable¹ • ≥50% of patients had undetectable plasma trough levels of each analyte on days
Slide 84: SYN-010 Clinical Outcomes
• Daily doses of SYN - 010 were well - tolerated by IBS - C patients over a 12 week treatment period in Phase 2a clinical trials¹ , ² • No SAEs, few TEAEs, no drug - related diarrhea • Compelling improvements were observed in bowel movement frequency, abdominal pain and bloating in IBS - C patients
Slide 85: Symptom Responses in the Open-Label Extension
• Placebo responses during the RCT • 0% Overall Response is possible if the CSBM response and abdominal pain response do not occur in the same week • Increased responses upon transition to the open - label EXT are not a Placebo effect of unblinding the dose • Increase in response was observed for al
Slide 86: SYN-010 Clinical Development Status
• FDA recommended a first Phase 2b/3 adaptive clinical trial • N=840 (280/arm) • Multicenter, randomized, double - blind, placebo - controlled study • Single daily doses of Placebo, SYN - 010 (21 mg) or SYN - 010 (42 mg) for 12 weeks • Both low and high - breath methane patients to be included • FDA
Slide 87: SYN-010 Pivotal Clinical Trials in IBS-C
SYN - 010 Pivotal Clinical Trials in IBS - C ¹Interim futility analysis based on dose may be conducted after 50% of subjects have completed 12 weeks. ²An Overall (12 - Week) Responder has a Weekly Response in at least 50% of weeks in the 12 - week treatment period. A Weekly Respons e is defined as a
Slide 88: Patient Stratification for Phase 2b/3 Clinical Trial
Single breath methane ≥5 ppm provides the same stratification of high - and low - methane producers as the full LBT¹ Single - point breath methane after overnight fast will be used for randomization Patient Stratification for Phase 2b/3 Clinical Trial ¹Gottlieb K et al. (2017) Gastroenterol Rep ( Ox
Slide 89: Why Include Low Breath Methane Patients?
IBS - C patients with low breath CH 4 but high gut CH 4 should also benefit from SYN - 010¹ Why Include Low Breath Methane Patients? ¹Kim G et al. (2012) Dig Dis Sci 57: 3213 - 8 ; the population prevalence of IBS - C patients with low breath CH 4 but constipating gut CH 4 has not been established.
Slide 90: SYN-010 Comparison to Other IBS-C Products
SYN - 010 Comparison to Other IBS - C Products Parameter SYN - 010 Linaclotide Lubiprostone Plecanatide Tenapanor Company Synthetic Biologics Allergan / Ironwood Takeda / Sucampo Synergy Ardelyx Brand -- Linzess® Amitiza® Trulance™ -- Current Status Phase 2b/3 Market Market Market Phase 3 Clinical T
Slide 91: SYN-010 key differentiators
• Novel mode - of - action, distinct from current IBS - C therapies • Treats a cause of IBS - C symptoms without causing diarrhea ‒ Low cost of goods enables payer - friendly pricing while retaining good margins • Proprietary formulation distinct from other statin products • Lovastatin lactone inhib