Immuron Limited · ASX:IMC
Immuron — AASLD 2018
22 slides from Immuron's conference presentation, 2018
Slide 1: IMM-124E Improves Metabolic Endotoxemia and Markers of Liver Injury in NASH
IMM-124E IMPROVES METABOLIC ENDOTOXEMIA AND MARKERS OF LIVER INJURY IN NONALCOHOLIC STEATOHEPATITIS Abdelmalek MF, Freilich BL, Harrison S, Powell EE, Rinella ME, Tobis N, Peres D, Kanellos J, Lalazar G, Sanyal AJ Study Sponsor: Immuron (NCT02316717)
Slide 2: Metabolic endotoxemia: a driver of systemic inflammation
Metabolic endotoxemia: a driver of systemic inflammation in obesity- insulin resistance-type 2 diabetes Fat Ox stress Cell death Lipotoxicity Inflammation UPR FFA Fibrosis INFLAMMATIORY PATHWAYS repair CALORIES ENDOTOXIN BACTERIAL METABOLITES microbiota Bile salts ileum Large bowel Friedman Tetri Ri
Slide 3: IMM-124E
IMM-124E • Colostrum from cattle vaccinated with pathogenic Enterotoxigenic E. coli (ETEC) (>35% IgG) Pre- Clinical • Orally active antibodies bind and neutralize endotoxins Studies • Reduces motility, adherence to host epithelium and colonization of pathogenic ETEC Without IMM-124E With IMM-124E De
Slide 4: Hypothesis: Decreasing metabolic endotoxemia with IMM-124E will reduce NASH progression
Hypothesis: Decreasing metabolic endotoxemia with IMM-124E will reduce the drivers of NASH progression Fat Ox stress Cell death Lipotoxicity Inflammation UPR FFA Fibrosis INFLAMMATIORY PATHWAYS repair CALORIES ENDOTOXIN BACTERIAL METABOLITES • ↓ ALT • ↓ CK18 • ↓ ? Steatosis IMM-124E Bile salts endot
Slide 5: Study Design
STUDY DESIGN: Prospective dose-ranging phase 2A trial 120 patients, 3-arms, Randomized, double blind, Placebo controlled 2-dose, balanced 1:1:1 design Treatment allocation stratified by diabetes status: HBA1C <6.0 versus HBA1C >6.0 and/or diagnosis of Type II diabetes 24 week treatment Placebo (TID)
Slide 6: Key Inclusion Criteria
Key Inclusion Criteria • Age ≥ 18 years • Diagnosis of NASH Histologically proven within 12 months of screening and all of the following criteria met: • NASH activity score (NAS) of 4 or more • Cytologic ballooning score of at least 1 • 10% or more macrovesicular steatosis • Hematoxylin & Eosin (H&E
Slide 7: Key Exclusion Criteria
Key Exclusion Criteria • Liver disease of other cause • Cirrhosis • BMI <25kg/m2 • Alcohol use >30g/day • Weight change of ≥ 10% in past 12 months • Other excluded conditions: T1DM, ongoing multi-systemic immune-mediated disease, concurrent or past malignant disease • Concurrent medications includin
Slide 8: Study Endpoints
Study Endpoints PRIMARY • Safety and tolerability (clinical) • Hepatic Fat Fraction SECONDARY • Markers of liver injury – ALT, AST, CK-18 • Glucose homeostasis • Serum Bovine Ig – Safety parameter • Establish recommended dose MoA • Lipopolysaccharides (LPS)
Slide 9: Results: Study Population
Results: Study Population Patients Screened N = 237 Screen Failures N = 104 Randomized N = 133 Full Analysis Set (FAS) Early Termination N = 21 Non compliance N=8 Major protocol Deviations Per Protocol (PP) = 102 N=2
Slide 10: Results: baseline characteristics
Results: baseline characteristics Placebo IMM-124E 600 mg IMM-124E 1200 mg P value (n=44) (n=43) (n=46) Age (yrs) 49.4 52.5 50.9 0.579 Females (%) 45.5 53.5 58.7 0.410 Caucasian (%) 76.3 72.4 88.6 0.236 T2 DM (%) 38.6 41.9 39.1 0.987 BMI (kg/m2) 34.7 33.8 34.2 0.786 AST (IU/l) 47.8 48.0 46.7 0.968 A
Slide 11: Results: baseline histology
Results: baseline histology Placebo IMM-124E IMM-124E P value (n=44) 600 mg (n=43) 1200 mg (n=46) steatosis 2.24 2.24 2.14 0.825 Lobular inflammation 1.71 1.59 1.66 0.647 Ballooning 1.39 1.45 1.5 0.598 Fibrosis 1.66 1.72 1.69 0.952 NAS 5.34 5.28 5.31 0.968 Individual parameters scored by NASH CRN sc
Slide 12: Primary outcome: Serious Adverse Events
Primary outcome: Serious Adverse Events Placebo IMM-124E IMM-124E (n=44) 600 mg (n=43) 1200 mg (n=46) Any 3 1 2 Chest pain 0 0 1 Motor vehicle accident 1 0 0 Elevated CPK 1 0 0 Transitional cell CA 0 1 0 Anxiety attacks 0 0 1 Psychiatric hospitalization 1 0 0 Rx stopped due to AE 0 1 1 Grade 3-4 1 1
Slide 13: Primary outcome: MRI-PDFF
Primary outcome: MRI-PDFF No significant changes n No o s Significant i g n i f i c a n tChanges changes 0 Placebo p l a c e b o (N=38) a s e lin e i o m bbaseline IMM-124E I m m - 1 2 4 600mg ( 6 0 0 m (N=29) g /d a y ) -1 IMM-124E I m m 1 2 4 (1200mg 1 2 0 0 m (N=39) g /d a y ) a n g e f rfrom c h
Slide 14: Secondary outcome: ALT
Secondary outcome: ALT Proportion with ≥30% decrease in ALT (Baseline ALT ≥50) % >30% decrease 10 40 P< 0.05 Change in ALT (UL) from Day 0 5 0 30 -5 % of Subjects with 20 -10 -15 10 -20 28 0 2856 56 8484 112 112 140 140 168 168 196 196 0 Study Day Study Day o g) g) eb m m 1200mg 600mg Pl a cebo ac 0
Slide 15: Markers of liver injury: IMM-124E improved AST
Markers of liver injury: IMM-124E improved AST P<0.05 5 Change in AST (UL) from Day 0 0 -5 -10 28 0 56 28 56 84 84 112 112 140 140 168 168 196 196 Study StudyDay Day 1200mg 600mg Pl a cebo 1200mg 600mg Pl a cebo LS Mean ± Std Err from RMMM on Change romDifferences RMMM on Change (p < 0.05): # Placeb
Slide 16: Change in Cytokeratin-18
Baseline to End of Treatment changes in CK 18 Proportion with ≥15% decrease in CK-18 5 P<0.05 p < 0 .0 5 % of subjects with ≥15% decrease Da...0 750 (UL) from Day 40 500 0 (pg/mL) 30 250 Change in AST Change in Cytokeratin-18 -5 0 % 20 -250 -10 10 -500 0 28 56 84 112 140 168 196 0 28 -750 56 84 Stud
Slide 17: IMM-124E does not impact insulin resistance (HOMA-IR)
IMM-124E does not impact insulin resistance (HOMA-IR) placebo IMM-124E IMM-124E 600 mg 1200 mg Mean Baseline 11.78 9.68 9.51 SD Baseline 9.84 6.76 8.04 Mean W24 10.84 11.37 9.89 SD W24 8.68 12.26 7.13 P value vs. Placebo 0.236 0.491
Slide 18: Mechanism of action related endpoints: IMM-124E decreased endotoxemia
Mechanism of action related endpoints: IMM-124E (1200 mg) decreased endotoxemia p = 0 .0 7 b y o r d in a l r e g r e s s io n pp =< 0.03 0 .0 2 100 100 > 15% in c r e a s e 80 w it h in 1 5 % o f b a s e lin e 80 > 15% d e c re a s e 60 60 % % 40 40 20 20 0 0 p la c e b o A c tiv e d r u g ) ) o g
Slide 19: LPS sensitivity analysis
LPS sensitivity analysis IMM-124E 1200mg (Wald # of # of test) events events improvement placebo p-value deterioration
Slide 20: Summary
Summary • IMM-124E was well tolerated and had no discernable toxicity • The systemic exposure to bovine IgG was minimal to none • IMM-124E did not improve hepatic steatosis • IMM-124E produced a dose-dependent improvement in endotoxemia and markers of liver injury (AST, ALT, CK 18)
Slide 21: Conclusions
Conclusions • The study provides proof of concept that metabolic endotoxemia can be improved with IMM-124E. • These provide a rationale to evaluate this compound in even higher doses in conditions where endotoxemia may be relevant e.g. alcohol-induced liver injury and cirrhosis.
Slide 22: Acknowledgments
Acknowledgments • Manal F. • Stephen Harrison • Mary E. Rinella Abdelmalek • Stephen H. • Bradley Freilich • Cynthia Guy Caldwell • Giuseppe Morelli • John Rawls • Amanda Wieland • Mitchel • Lawrence David • Kris Kowdley Shiffrman • Mohammad Shadab • Rohit Loomba • Robert Stuart Siddiqui • Angelo Hu