Slide 1: Results from Two Phase 2 Clinical Trials of SYN-010
Mark Pimentel, MD, FRCP(C) Results from Two Phase 2 Clinical Trials of SYN - 010, a Proprietary, Modified - Release Formulation of Lovastatin Lactone Designed to Reduce Methane Production in the Gut to Treat an Underlying Cause of IBS - C. May 23, 2016
Slide 2: Forward-Looking Statements
2 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: Irritable Bowel Syndrome (IBS): Chronic Functional Gastrointestinal Disorder
3 • Gas, abdominal pain, bloating and abnormal bowel movements • IBS - C constipation - predominant (30%) • IBS - D diarrhea - predominant (30%) • IBS - M (or A) mixed (alternating) • IBS - U unsubtyped • 15% of the world’s population suffers from IBS • 30 - 40 million people in the USA • 50% of vis
Slide 4: Seeking Normalization of Bowel Habits
4 CONSTIPATION NORMAL DIARRHEA SYN - 010: Seeking Normalization of Bowel Habits Relief of Constipation, Pain and Bloating Without Diarrhea SYN - 010 Laxatives Lubiprostone Linaclotide SYN - 010 Laxatives Lubiprostone Linaclotide Treating the Cause
Slide 5: Overview: Anti-Methanogenic Therapy to Normalize Bowel Habits
5 SYN - 010 Overview • Intestinal methane (CH 4 ) is causative of constipation in IBS - C and chronic idiopathic constipation • Key intellectual property licensed from Cedars - Sinai Medical Center • SYN - 010 is a proprietary, modified - release formulation of lovastatin lactone for use in IBS - C
Slide 6: Modified Release Formulation of Lovastatin
6 SYN - 010 Modified Release Formulation of Lovastatin • Capsule formulation containing lovastatin lactone • Optimal statin anti - methanogenic species • Designed to avoid lovastatin release into the stomach • Minimize conversion of anti - methanogenic lovastatin lactone to the cholesterol lowering
Slide 7: Comprehensive Patent Strategy
7 SYN - 010 Phase 2 Trial Completion/Phase 3 Initiation Projected ~2016 Patented Methods of Treatment (Broadest Indication) Expires 2023 Patented and Pending Methods of Treating Constipation with SYN - 010 in Screened Patients Expires 2034 Pending Patent Applications on SYN - 010 Formulations, Metho
Slide 8: Phase 2 Clinical Trials
SYN - 010 Phase 2 Clinical Trials
Slide 9: Patients Evaluated in 2 Contiguous Studies
9 Subjects who successfully completed Study 1 were transferred to active drug at Day 29 SYN - 010 Evaluated in IBS - C Patients in 2 Contiguous Studies Weeks 1 - 4 Randomized, Blinded, Placebo - Controlled; Weeks 5 - 12 Open Label SYN - 010 21 mg (22) Placebo (22) SYN - 010 42 mg (19) | | | | | | |
Slide 10: Monthly Responder as Defined by FDA
10 Monthly Responder as Defined by FDA • Monthly Responder* is FDA - recommended endpoint in clinical trials for Irritable Bowel Syndrome with Constipation (IBS - C) • A Monthly Responder is defined as a subject who has a weekly response in at least 50% of the weeks of treatment during the month • A
Slide 11: Study 1
SYN - 010 Study 1
Slide 12: Study 1: Anti-Methanogenic Effect Overview
12 Study 1: SYN - 010 Anti - Methanogenic Effect in IBS - C Patients • Randomized, double - blind, parallel - group, placebo - controlled study in breath methane positive IBS - C patients • 12 centers in the United States • Compared SYN - 010 21 mg and 42 mg with placebo • 28 days of single, daily d
Slide 13: Study 1: Inclusion and Exclusion Criteria
13 • Key Inclusion Criteria • IBS - C (modified Rome III) • Breath methane >10 ppm at Screening • Compliance with 7 - day Diary Screening • Discontinue laxatives, medications, supplements intended to treat constipation • Refrain from lifestyle changes that may affect IBS - C symptoms (e.g. new diet)
Slide 14: Study 1: Subject Demographics
14 Study 1: SYN - 010 Anti - Methanogenic Effect in IBS - C Patients Subject Demographics Parameter Treatment Group Dose (oral, q.d .) Placebo SYN - 010 21 mg SYN - 010 42 mg Female, n/total (%) 17/22 (77.3%) 19/22 (86.4%) 14/19 (73.7%) Age , years* 46.4 ± 10.3 42.6 ± 6.0 44.7 ± 9.5 Race, n (%) Whit
Slide 15: Study 1: Changes in Breath Methane AUC Relative to Baseline
15 - 10.6 - 31.0 11.1 - 22.6 - 34.6 - 34.3 -120 -100 -80 -60 -40 -20 0 20 40 60 80 Change in Breath Methane AUC (ppm*h) Placebo SYN-010 21 mg SYN-010 42 mg Study 1: SYN - 010 Anti - Methanogenic Effect in IBS - C Patients SYN - 010 Changes in Breath Methane AUC Relative to Baseline ( mITT ) p=0.64 p
Slide 16: Study 1: Effects on Response Rates
16 Study 1: SYN - 010 Effects on Response Rates SYN - 010 Effects on Weekly Responses ( mITT ) *P - value based an a Wilcoxon Mann - Whitney test for the comparison of SYN - 010 treatment to Placebo. Error bars are SD. P=0.028* P=0.155 % Subjects with Monthly Response † Placebo: 0% SYN - 010 21 mg:
Slide 17: Study 1: Use of Rescue Medication
17 Study 1: Use of Rescue Medication Lower use of Rescue Medication for SYN - 010 vs. Placebo ( mITT ) *p=0.013 vs Placebo † p =0.03 vs Placebo Fisher’s exact test % Subjects using RLax ® ( bisacodyl ; 5 mg) in Study 1 4/22* 4/19 † 12/22 Daily use of RLax ® ( bisacodyl ; 5 mg) in Study 1 >60% Less R
Slide 18: Study 1: Well Tolerated
18 Study 1: SYN - 010 Well Tolerated in IBS - C Patients Treatment Emergent Adverse Events (TEAEs) Placebo SYN - 010 21 mg SYN - 010 42 mg Withdrawals 2 2 2 Serious AEs 0 0 0 TEAEs 1 (4.5%) 1 (4.5%) 2 (10.5%) Type Gastroenteritis Headache 1. Elevated GGT 2. Elevated AST, CPK Severity Moderate Mild 1
Slide 19: Study 1: Lovastatin Plasma Levels
19 Study 1: SYN - 010 Lovastatin Plasma Levels in IBS - C Patients • SYN - 010 exerts its anti - methanogenic IBS - C therapeutic effect in the intestinal lumen • Systemic exposure to lovastatin lactone and/or β - hydroxyacid are not required for the treatment of IBS - C • ≥ 50% of subjects in each
Slide 20: Study 1: Summary of Clinical Outcomes
20 Study 1: Summary of SYN - 010 Clinical Outcomes • SYN - 010 was well tolerated in breath methane positive IBS - C patients treated with single, daily, oral doses of 21 mg or 42 mg for 28 days • SYN - 010 reduced breath methane from baseline in breath methane positive IBS - C patients • SYN - 010
Slide 21: Study 2
SYN - 010 Study 2
Slide 22: Patients Evaluated in 2 Contiguous Studies
22 Subjects who successfully completed Study 1 were transferred to active drug at Day 29 SYN - 010 Evaluated in IBS - C Patients in 2 Contiguous Studies Weeks 1 - 4 Randomized, Blinded, Placebo - Controlled; Weeks 5 - 12 Open Label SYN - 010 21 mg (22) Placebo (22) SYN - 010 42 mg (19) | | | | | | |
Slide 23: Study 2: Extension Study Overview
23 Study 2: SYN - 010 in IBS - C Patients, 8 Week Extension Study • Open - label, 8 week study in 54 of the 57 IBS - C patients who successfully completed the randomized, placebo - controlled 4 week study (Study 1) • Eligible participants transferred to daily doses of SYN - 010 42 mg • Primary objec
Slide 24: Study 2: Changes in Breath Methane vs Study 1 Baseline
24 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks Treatment SYN - 010 Changes in Breath Methane vs Study 1 Baseline (Day 1) 7 28 35 84 -- -- 35 84 7 28 35 84 7 28 35 84 *P=0.002 vs Day 1 *P=0.018 vs Day 1 P=0.084 vs Day 1 P=0.07 vs Day 28 *Paired t - test vs Day 1; data normalized (square root) pr
Slide 25: Study 2: Inverse Correlation Between Breath Methane AUC and Bowel Movements
25 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment Inverse Correlation Between Breath Methane AUC and Bowel Movements Data are for all IBS - C patients at Week 12 (at least 8 weeks of SYN - 010 42 mg) • Higher breath methane AUC associated with fewer complete spontaneous bowel movement
Slide 26: Study 2: Changes in Percentage of Monthly Responders
26 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment SYN - 010 Changes in Percentage of Monthly Responders Month 1| 2 | 3 Month 1| 2 | 3 Month 1 | 2 | 3 Month -- | 2 | 3 Dose Month 1 Dose Months 2,3
Slide 27: Study 2: Responders Increased over Time on 42 mg
27 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment % Responders Increased over Time when Transferred to SYN - 010 42 mg Study Period % Subjects With a Response at Indicated Week SYN - 010 Dose (oral, q.d .) Weeks 1 - 4 / 5 - 12 Placebo / 42 mg 21 mg / 42 mg 42 mg / 42 mg Increase of ≥1
Slide 28: Study 2: Changes in IBS Symptom Severity Score
28 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment SYN - 010 Changes in IBS Symptom Severity Score vs Study 1 Baseline (Day 1) Dose Days 1 - 28 Dose Days 29 - 84 *P=0.0042 *P <0.0001 *Paired t - test vs Baseline (Day 1). *P=0.0018 *P=0.0012 Day 1 | 28 | 84 Day 1 | 28 | 84 Day 1 | 28 |
Slide 29: Study 2: Effects on Subjects with Elevated Lipids
29 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment SYN - 010 Effects on Percentage of Subjects with Elevated Lipids Dose Days 1 - 28 Dose Days 29 - 84 Triglycerides Cholesterol LDL - C SYN - 010 Dose Baseline Value (mean ± SD [n] mmol /L) Days 1 - 28 / 29 - 84 Cholesterol LDL - C Trigl
Slide 30: Treatment Emergent Adverse Events (TEAEs)
30 SYN - 010 in IBS - C Patients over 12 Weeks Treatment Emergent Adverse Events (TEAEs) Placebo / 42 mg 21 mg / 42 mg 42 mg / 42 mg Withdrawals Weeks 5 - 12* 1 (AE) 2 (Other) 2 (Other) Serious AEs Weeks 1 - 4 Weeks 5 - 12 0 0 0 0 0 0 TEAEs Weeks 1 - 4 Weeks 5 - 12 1. Gastroenteritis 2. Diarrhea 3.
Slide 31: Summary of Clinical Outcomes
31 SYN - 010 Summary of Clinical Outcomes • SYN - 010 was well tolerated in breath methane positive IBS - C patients treated with daily oral doses of SYN - 010 42 mg for up to 12 weeks • SYN - 010 reduced breath methane from baseline in breath methane positive IBS - C patients • SYN - 010 improved I
Slide 32: Pharmacokinetics
SYN - 010 Pharmacokinetics
Slide 33: Study 3: Pharmacokinetics in Healthy Volunteers
33 Study 3: SYN - 010 Pharmacokinetics in Healthy Volunteers • Randomized, open - label study in heathy volunteers • 8 volunteers per group; 1 center in the United States • Compared SYN - 010 21 mg, 42 mg and 84 mg • Single daily doses x 4 days, administered after overnight fast • Plasma samples col
Slide 34: Study 3: Pharmacokinetic Profile after a Single Dose
34 Study 3: SYN - 010 Pharmacokinetics in Healthy Volunteers SYN - 010 Pharmacokinetic Profile after a Single Dose (Preliminary Data) Lactone β - Hydroxyacid L ag time to first plasma levels • Drug not released in the stomach Increasing plasma levels out to 24 h • Drug release well into the colo
Slide 35: Therapeutic Opportunity
SYN - 010 Therapeutic Opportunity
Slide 36: Comparison to Competitor Therapies
36 SYN - 010 Comparison to Competitor Therapies SYN - 010 has a Similar Overall Response Rate* Without Causing Diarrhea Drug Overall Response* Defined as ≥30% decrease in weekly average abdominal pain score AND an increase in ≥1 CSBM per week vs baseline in ≥50% of the weeks of treatment. *Response
Slide 37: Normalization of Bowel Habits
37 CONSTIPATION NORMAL DIARRHEA SYN - 010: Normalization of Bowel Habits Relief of Constipation, Pain and Bloating Without Diarrhea SYN - 010 Laxatives Lubiprostone Linaclotide SYN - 010 Laxatives Lubiprostone Linaclotide Treating the Cause
Slide 38: Multiple Prescribing Opportunities
38 SYN - 010 Multiple Prescribing Opportunities • Stand - alone chronic therapy • Continuous low doses • Pulsatile high doses • High - dose induction then low dose maintenance • Concomitant therapy with other modalities • Mechanism of action distinct from current IBS - C medicines • Follow - up ther
Slide 39: Progress to Phase 3 Registration Studies
39 SYN - 010 Progress to Phase 3 Registration Studies • End of Phase 2 Meeting with FDA planned for Summer 2016 • Seek agreement on study design and endpoints • Seek agreement of 505(b)2 strategy • Phase 2 data suggest potential efficacy of both SYN - 010 21 mg and 42 mg • Advance 2 dose levels (pre
Slide 40: SYN - 010
SYN - 010
Slide 41: Study 2: Changes in Bloating Score vs Study 1 Baseline
41 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment SYN - 010 Changes in Bloating Score vs Study 1 Baseline (Day 1) Week 4 | 8 | 12 Week 4 | 8 | 12 Week 4 | 8 | 12 Week -- | 8 | 12 Dose Weeks 1 - 4 Dose Weeks 5 - 12 *P<0.0001 vs Day 1 † P<0.0001 vs Day 28 *P=0.0017 † P=0.0032 *P=0.0001
Slide 42: Study 2: Changes in Abdominal Pain Score vs Study 1 Baseline
42 Study 2: SYN - 010 in IBS - C Patients, 12 Weeks of Treatment SYN - 010 Changes in Abdominal Pain Score vs Study 1 Baseline (Day 1) Week 4 | 8 | 12 Week 4 | 8 | 12 Week 4 | 8 | 12 Week -- | 8 | 12 Dose Weeks 1 - 4 Dose Weeks 5 - 12 *P<0.0001 vs Day 1 † P<0.0001 vs Day 28 *P=0.0001 † P=0.0082 *P<0
Slide 43: Results from Two Phase 2 Clinical Trials of SYN-010
Mark Pimentel, MD, FRCP(C) Results from Two Phase 2 Clinical Trials of SYN - 010, a Proprietary, Modified - Release Formulation of Lovastatin Lactone Designed to Reduce Methane Production in the Gut to Treat an Underlying Cause of IBS - C. May 23, 2016 Post - DDW SYN - 010 Phase 2 Clinical Trial Res