1. BACKGROUND. Lovastatin β-hydroxyacid No effect on methane production Inhibits cholesterol synthesis
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1 1. BACKGRUND Methane production by the archeon Methanobrevibacter smithii (M. smithii) is a ubiquitous process in the intestine, disposing of hydrogen and other by-products formed during carbohydrate digestion by bacteria¹ Clinical and preclinical evidence have demonstrated that elevated intestinal methane production reduces gut motility and is an underlying cause of symptoms in irritable bowel syndrome with constipation (IBS-C)² Methane production by M. smithii in stool from IBS-C patients is inhibited by lovastatin lactone, but not by its β-hydroxyacid metabolite or other statins³ Stomach acid; Esterases Lovastatin lactone Inhibits methane production No effect on cholesterol synthesis Lovastatin β-hydroxyacid No effect on methane production Inhibits cholesterol synthesis ¹Gottlieb K et al. (2015) Aliment Pharmacol Ther 43: ²Triantafyllou K et al. (2014) J Neurogastroenterol Motil 20: ³Marsh E et al. (2015) Am J Gastroenterol 110 (Suppl 1): S753
2 2. BJECTIVES SYN-010 is a proprietary, modified-release formulation of lovastatin lactone, designed to reduce intestinal methane production and alleviate IBS-C symptoms without causing gross disruption of the microbiome (Figure 1) SYN-010 exerts its antimethanogenic effect in the intestine, so systemic absorption of lovastatin species from the SYN-010 formulation is not required In previous Phase 2a clinical trials, daily oral doses of SYN mg and 42 mg alleviated symptoms in a significant number of IBS-C patients¹, ² Increased bowel movement frequency, reduced abdominal pain score, improved bloating score, no drug-related diarrhea The current study evaluated the plasma pharmacokinetics and stool drug levels of lovastatin lactone and β-hydroxyacid in healthy volunteers administered daily oral doses of SYN mg, 42 mg and 84 mg Investigate the proposed drug release profile of the SYN-010 formulation Explore systemic exposure to lovastatin species after SYN-010 administration Determine whether methane-inhibiting levels of lovastatin lactone are delivered to the intestine by the SYN-010 formulation Advise whether additional SYN-010 doses should be tested in IBS-C clinical trials ¹Gottlieb K et al. (2015) Gastroenterol 150: S-496 ²Wacher V et al. (2016) Am J Gastroenterol 111 (Suppl 1): S256-7
3 SYN-010 Modified Release Lovastatin Lactone Figure 1: SYN-010 comprises a capsule containing combinations of lovastatin lactone tablets coated with different enteric polymers to prevent drug release in the stomach then deliver different lovastatin lactone doses to the duodenum (DR; blue tablet) and the ileocecal junction/colon (ICR) SYN mg Stomach Duodenum Jejunum Ileum Cecum Colon p p p p p p C 4 2 C 4 Bacterial overgrowth M. smithii overgrowth Bacteria M. smithii Bacteria M. smithii Capsule dissolves and enteric coatings prevent hydrolysis of lovastatin lactone¹ Duodenal release (DR) tablet disintegrates to release active lovastatin lactone in the duodenum Ileocecal release (ICR) tablets disintegrate to release active lovastatin lactone into the ileocecal junction and colon Reduce methane without killing microbes ¹Gastric absorption accounts for up to 30% of an immediate-release lovastatin dose; avoiding the stomach and preserving lovastatin in the lactone form is expected to lower systemic levels of the cholesterol-lowering β-hydroxyacid metabolite
4 3. CLINICAL STUDY DESIGN Fasted, healthy volunteers were randomly assigned to receive single oral doses of SYN mg, 42 mg or 84 mg each day for 4 days (Table 1)¹ Plasma samples were collected from all participants on day 1 (0-24 h) and day 4 (0-32 h) and stool samples were collected on each dosing day Plasma and stool samples were analyzed for lovastatin lactone and β-hydroxyacid using an LC-MS/MS method Potential systemic effects of SYN-010 were evaluated by measuring serum lipid parameters and markers of liver and muscle function Table 1: SYN-010 capsule configurations; ratio is DR:ICR tablets SYN mg SYN mg SYN mg + 1:2 1:5 2:10 ¹Doses were administered each morning after an overnight fast of at least 10 h and food was not restored until at least 2 h after the SYN-010 dose
5 4. RESULTS SYN-010 was well-tolerated at all doses and the few reported adverse events were all of mild intensity (Table 2) No serious adverse events were reported and no diarrhea was observed SYN-010 plasma pharmacokinetic profiles were consistent with negligible drug release in the stomach, followed by dual pulse release of different drug doses in the duodenum and the ileocecal region/colon (Figures 2, 3) Lovastatin β-hydroxyacid C max and AUC 0-24 for a single dose of SYN mg were ~50% of the values reported for single 40 mg doses of commercial lovastatin formulations (Mevacor, Altoprev )¹ in fasted healthy volunteers Lovastatin lactone stool levels on day 4 of SYN-010 dosing were equivalent to concentrations that inhibited methane production by 60% (21 mg) and 90% (42, 84 mg) in stool samples from IBS-C patients in vitro (Figures 4, 5) Stool concentrations of lovastatin lactone were >> β-hydroxyacid, consistent with limited presystemic conversion of lactone to β-hydroxyacid SYN mg and 42 mg doses did not cause meaningful changes to serum lipid parameters; however, reductions in cholesterol and triglycerides were observed with SYN mg (Table 3, Figure 6) ¹A head to head comparison was not conducted in this study; data for Mevacor and Altoprev are from
6 SYN-010 Pharmacokinetic Study Population Table 2: Baseline demographics and adverse event profile for subjects in the pharmacokinetic study Parameter SYN mg SYN mg SYN mg Baseline Demographics¹ No. Subjects (Female %) 8 (50%) 8 (50%) 8 (87.5%) White / Black, African American, % 87.5% / 12.5% 100% / % / 37.5% Age, years 51.1± ± ±15.3 Body weight, kg 81.2± ± ±16.1 BMI, kg/m² 28.9± ± ±3.0 Dose, mg/kg 0.26± ± ±107 Study drug compliance 100% 100% 100% Treatment Emergent Adverse Events² Withdrew, n Reported SAE, n Reported TEAE, n Description of TEAE (relationship to treatment)³ 01 Somnolence (probable) 02 eadache (probable) 03 Flatulence (probable) 04 eadache (possible) 05 Dyspepsia (probable) ¹Data are mean±sd unless indicated ²SAE = serious adverse event, TEAE = treatment emergent adverse event; numbers are masked Subject ID
7 SYN-010 Plasma Pharmacokinetics Day 1 Figure 2: Plasma levels of lovastatin lactone and β-hydroxyacid after one dose of SYN-010 (day 1) Lactone β-ydroxyacid 3 h delay until first visible plasma concentrations indicates negligible drug release in the stomach Continually increasing plasma levels over 24 h are consistent with drug release well into the colon Lovastatin β-hydroxyacid C max and AUC for the 42 mg dose are ~50% of the values reported for 40 mg doses of commercial lovastatin formulations evaluated in fasted healthy volunteers² Dose (n) C max (ng/ml)¹ AUC 0-24 (ng.h/ml)¹ Lactone -Acid Lactone -Acid SYN mg (8) 1.7± ±0.7 21±19 12±6 SYN mg (8) 2.7± ±1.6 35±41 19±20 SYN mg (8) 6.0± ±1.8 79±55 33±16 Mevacor 40 mg² 2.8± ±1.8 38±18 44±17 Altoprev 40 mg² 3.4± ±1.9 54±20 58±20 ¹Data are mean±sd (n=8); PK parameters calculated using noncompartmental methods ²A head to head comparison was not conducted in this study; data for Mevacor and Altoprev are from
8 SYN-010 Plasma Pharmacokinetics Day 4 Figure 3: Plasma lovastatin lactone and β-hydroxyacid levels after 4 doses of SYN-010 (day 4) Lactone β-ydroxyacid Steady state plasma levels appear to have been reached after 4 days of dosing The proposed dual pulse lovastatin lactone release profile is evident in the plasma concentration vs time profiles Lovastatin β-hydroxyacid plasma levels largely track with lactone levels, suggesting conversion of lactone to the β-hydroxyacid is predominantly systemic (post-absorption) Dose (n) C max (ng/ml)¹ AUC 0-32 (ng.h/ml)² Lactone -Acid Lactone -Acid SYN mg (8) 2.6± ±0.6 41±42 34±13 SYN mg (8) 3.6± ±4.1 76±41 63±76 SYN mg (8) 8.3± ± ± ±98 ¹Data are mean±sd; PK parameters calculated using noncompartmental methods. ²Area under the concentration vs time curve from 0-32 h (AUC 0-32 ) calculated using he linear trapezoidal method
9 SYN-010 Stool Concentrations Days 2-4 Figure 4: Stool levels of lovastatin lactone and β-hydroxyacid in samples collected on days 2-4 Lactone β-ydroxyacid (1/10 the scale of lactone) Antimethanogenic lovastatin lactone is the predominant lovastatin species in stool Day 4 lovastatin lactone stool levels were not significantly higher for SYN mg compared to SYN mg Lovastatin β-hydroxyacid stool levels were the same for the 21 mg and 42 mg doses, suggesting that stool β- hydroxyacid levels are largely determined by the DR component of the formulation Dose Lactone / β-hydroxyacid (n)¹ Day 2 Day 3 Day 4 SYN mg 14±13 (7) 28±38 (6) 10±12 (6) SYN mg 72±69 (5) 27±43 (7) 28±24 (7) SYN mg 40±49 (6) 18±24 (8) 13±17 (6) ¹Data are mean±sd *P<0.05 vs 21 mg, P<0.1 vs 21 mg, P<0.1 vs 42 mg (unpaired t-test)
10 Lovastatin Lactone Inhibits Methane Production in Stool Figure 5: Comparison of lovastatin lactone concentrations measured in the stool of healthy volunteers in vivo with lovastatin lactone concentrations used to inhibit methane production by stool samples from IBS-C patients in vitro¹ 5A: Lovastatin lactone ( mg/g stool wet weight) was incubated for 270 min in homogenates made from stool samples provided by high breath C 4 IBS-C patients¹. C 4 was measured in the reactor headspace using gas chromatography. To account for baseline variability, data are presented as change from time 0 ΔC 4 = C 4 at time (n) C 4 at time 0. 5B: A plot of ΔC 4 AUC (expressed as % of control) vs the inverse of lovastatin lactone stool concentration shows that lovastatin lactone concentrations in the stool of healthy volunteers were equivalent to concentrations that inhibited C 4 production in stool from IBS-C patients ΔC 4 AUC = area under the ΔC 4 concentration vs time curve from min (figure 5A) ¹Marsh E et al. (2015) Am J Gastroenterol 110 (Suppl 1): S753
11 Serum Chemistry Parameters Parameter (Units, normal range) ALT (U/L, 8-54) GGT (U/L, 5-85) Table 3: Serum chemistry parameters for subjects in the pharmacokinetic study Creatine Kinase (U/L, ) Cholesterol (mmol/l, ) DL-C (mmol/l, ) LDL-C (mmol/l, ) Triglycerides (mmol/l, ) Day SYN mg SYN mg SYN mg Δ 1 5 Δ 1 5 Δ 1 5 Δ 1 5 Δ 1 5 Δ 25 (15-39) 24 (14-40) 23.0 (11-40) 22.5 (10-34) (66-168) 56.5 (53-72)* 46.6% 5.22 ( ) 5.15 ( )* 5.2% 1.55 ( ) 1.30 ( )* 11.4% 3.08 ( ) 3.19 ( ) 1.44 ( ) 1.41 ( ) 18 (11-29) 18 (13-26) 23.5 (11-43) 20.5 (9-29)* 18.5% (75-221) 61.0 (40-81)* 47.6% 4.67 ( ) 4.34 ( )* 5.5% 1.26 ( ) 1.13 ( ) 3.06 ( ) 2.73 ( )* 7.3% 1.20 ( ) 1.29 ( ) 18 (9-36) 22 (10-37) 19.5 (9-26) 15.5 (8-20)* 14.5% 93.5 (52-204) 55.0 (41-129)* 34.5% 4.80 ( ) 3.92 ( )* 17.1% 1.22 ( ) 1.18 ( )* 10.7% 2.64 ( ) 2.19 ( ) 15.0% 1.07 ( ) 0.88 ( )* 25.3% ¹Data are median (range). Δ=Mean percentage change from Day 1 to Day 5. *P<0.05, P<0.1 vs Day 1 (paired t-test)
12 Changes in Cholesterol and LDL-C vs SYN-010 Dose Figure 6: Trend to alteration of serum lipid parameters at the SYN mg dose
13 5. CNCLUSINS Previous Phase 2a clinical trials showed that daily oral doses of SYN mg and 42 mg were well-tolerated and provided symptom improvements in a significant number of IBS-C patients¹, ² The present study found that SYN mg, 42 mg and 84 mg doses were well-tolerated in healthy volunteers over a 4-day dosing period and affirmed the proposed dual pulse lovastatin lactone release profile The present study also demonstrated that the SYN mg and 42 mg doses used in Phase 2a clinical trials are appropriate doses for continued clinical evaluation in larger Phase 2b/3 studies Stool concentrations suggest that SYN-010 doses less than 21 mg may not deliver effective methane-inhibiting lovastatin lactone levels to the intestine, while doses higher than 42 mg are not needed for inhibition of methane production Plasma pharmacokinetics and serum chemistry suggest that SYN-010 doses higher than 42 mg may deliver systemic levels of lovastatin species that could cause unnecessary alterations to liver and lipid parameters A Phase 2b/3 adaptive clinical trial design evaluating SYN mg and 42 mg doses in IBS-C patients for 12 weeks has been discussed with the FDA ¹Gottlieb K et al. (2015) Gastroenterol 150: S-496 ²Wacher V et al. (2016) Am J Gastroenterol 111 (Suppl 1): S256-7
14 JDDW CNFLICT-F-INTEREST DISCLSURE Authors: Vince Wacher; John Kokai-Kun; livia Coughlin; Candy Lionetti; Klaus Gottlieb; Joseph Sliman Affiliation: Synthetic Biologics, Inc., Rockville, MD, USA (all authors) CI Related to this Presentation: 1 Advisor: 2 Stock wnership/profits: 3 Royalties: 4 Lecture Fees: 5 Manuscript Fees: 6 Consigned/Joint Research Expenses: 7 Scholarship Donations: 8 Course Affiliations: VW is a consultant to Synthetic Biologics All authors are/were eligible for stock options None None None None None None 9 Gifts, ther Remuneration: JK-K, C, JS are Synthetic Biologics employees and CL, KG were employees at the time of the research
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