AASLD Oral late-breaker: Icosabutate in NASH/MASH with Fibrosis

Icosabutate in NASH/MASH with Fibrosis: Results from a Randomized, Multicentre, Double-Blind, Placebo Controlled, Phase 2 b Trial (ICONA) S.A. Harrison1,2, N. Alkhouri3, J.Benun4, G. Ortiz-Lasanta5, M. Rudraraju2, H. H. Steineger6, D. A. Fraser6, A. Sanyal7 & ICONA Study Investigators 1 Radcliffe Department of Medicine, University of Oxford, 2 Pinnacle Clinical Research, San Antonio, 3 Arizona Liver Health, 4 Pinnacle Clinical Research, Austin, 5 FDI Clinical Research, 6 Northsea Therapeutics, 7 Virginia Commonwealth University Richmond VA Dr Stephen A. Harrison, MD, COL (Ret.), FAASLD Visiting Professor of Hepatology Radcliffe Department of Medicine, University of Oxford Chairman and Founder, Pinnacle Clinical Research Chairman and Co-Founder, Summit Clinical Research Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Disclosures Stephen A. Harrison I disclose the following financial relationship(s) with a commercial interest: • Scientific advisor or consultant for Akero, Aligos, Altimmune, Arrowhead, Boxer Capital, Chronwell, Echosens, Foresite Labs, Galectin, Galecto, Gilead, GSK, Hepagene, Hepion, Hepta Bio, HistoIndex, Humana, Intercept, Ionis, Inventiva, Madrigal, Medpace, Merck, NeuroBo Pharmaceuticals, Northsea, Novo Nordisk, Perspectum, Pfizer, Sonic Incytes, Sagimet, Terns, Viking. • Stock options: Akero, Chronwell, Galectin, Hepion, Hepta Bio, HistoIndex, Northsea • Grant/Research support: Akero, Altimmune, Axcella, BMS, Corcept, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, GSK, Hepion, Hightide, Immuron, Intercept, Inventiva, Ionis, Madrigal, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Poxel, Sagimet, Terns, Viking. Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Icosabutate Structure and Target Receptor Profile Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Liver targeting (portal vein transport from gut) Structural modifications ensure: Avoidance of use as energy source Avoidance of esterification into cell membranes/storage Free-fatty acid receptor (FFAR)1 Target receptors: FFAR4 (b-arrestin2) PPAR-a (partial agonist) Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Targeting Insulin Resistance and Liver Inflammation via FFAR1/FFAR4 (GPR40/GPR120) Pancreatic b-cells GLP-1 FFAR4 FFAR1 FFAR1 GLP-1R Insulin FFAR4 LPS TNFɑ TLR4 TNFR TAK1 FFAR4 b-arrestin2 IKKβ MKK4 NFκB JNK Kupffer cells Inflammatory cytokines GlucoseGlucose uptake Insulin receptor Lipid storage FFAR4 GLUT4 PI3K Gq/11 TAB1 βarr2 Adipocytes Intestinal L-cells GLP-1 secretion Insulin secretion Anti- inflammatory Improved insulin resistance KEY ELIGIBILITY CRITERIA MASH on biopsy: MASH + NAS ≥4 Fibrosis stage F1 or F2 or F3 ≥8% hepatic fat by MRI-PDFF Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Icosabutate: Phase 2b Design (ICONA) R Placebo (n=92) Icosabutate 300 mg (n=93) Icosabutate 600 mg (n=95) 52-week double-blind treatment period Interim Analysis at Week 16 MASH Resolution with no worsening of fibrosis Primary Endpoint ≥ 1 stage improvement in fibrosis with no worsening of MASH Secondary Endpoints Liver chemistry, fibrosis, metabolic and inflammatory biomarkers Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. ICONA – Study Population Randomized Placebo (n=92) Icosabutate 300 mg (n=93) Icosabutate 600 mg (n=95) Placebo (n=75) Icosabutate 300 mg (n=76) Icosabutate 600 mg (n=77) Biomarker Analysis Set (n=228) Placebo (n=62) Icosabutate 300 mg (n=58) Icosabutate 600 mg (n=67) mITT Analysis Set (n=187) Not dosed or No 52 weeks biopsy Ineligible per 3-member panel read Placebo (n=59) Icosabutate 300 mg (n=57) Icosabutate 600 mg (n=62) PP Analysis Set (n=178) Protocol breach: GLP1-RA use or Low compliance Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. ICONA – Baseline Characteristics (mITT) Characteristic Placebo (N=75) 300 mg (N=76) 600 mg (N=77) Age, years 54 53 52 Female 69% 72% 66% Hispanic or Latino 43% 41% 38% Type 2 Diabetes Mellitus 47% 53% 51% BMI, kg/m2 35.9 36.7 37.3 Liver Fat Content, % by MRI-PDFF 19.9% 20.0% 19.5% Fibrosis score (F2/F3) 76% 82% 77% NAS 5.3 5.5 5.2 ALT, U/L 64.1 69.9 67.1 AST, U/L 49.3 56.8 45.6 hsCRP, mg/L 6.7 8.1 7.7 Pro-C3, ng/mL 19.6 20.8 18.9 ELF 9.96 9.91 9.77 Data are mean or % Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. ICONA – Histology Endpoints Per Protocol NASH Resolution with No worsening of Fibrosis 13.6% 19.3% 25.8% Placebo N=59 Icosa 300 mg N=57 Icosa 600 mg N=62 p=0.23 p=0.07 Primary Endpoint NASH Resolution with No worsening of Fibrosis 14.5% 19.0% 23.9% Placebo N=62 Icosa 300 mg N=58 Icosa 600 mg N=67 p=0.19 p=0.13 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Per Protocol NASH Resolution with No worsening of Fibrosis & ≥ 2-point decrease in NAS 11.9% 15.8% 25.8% Placebo N=59 Icosa 300 mg N=57 Icosa 600 mg N=62 p=0.23 p=0.03 Primary Endpoint NASH Resolution with No worsening of Fibrosis ICONA – Histology Endpoints 14.5% 19.0% 23.9% Placebo N=62 Icosa 300 mg N=58 Icosa 600 mg N=67 p=0.19 p=0.13 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Superior Effect in Type 2 Diabetes NASH Resolution with No worsening of Fibrosis & ≥ 2-point decrease in NAS NASH Resolution with No worsening of Fibrosis 4.3% 14.3% 35.5% Placebo N=23 Icosa 300 mg N=28 Icosa 600 mg N=31 p=0.23 p=0.007 8.7% 17.9% 35.5% Placebo N=23 Icosa 300 mg N=28 Icosa 600 mg N=31 p=0.35 p=0.02 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Superior Effect in Type 2 Diabetes T2DM ≥ 1-stage improvement in Fibrosis with no worsening of NASH Overall Population ≥ 1-stage improvement in Fibrosis with no worsening of NASH 11.9% 26.3% 22.6% Placebo N=59 Icosa 300 mg N=57 Icosa 600 mg N=62 p=0.07 p=0.13 0.0% 28.6% 19.4% Placebo N=23 Icosa 300 mg N=28 Icosa 600 mg N=31 p=0.005 p=0.02 93% F2/F3 74% F2/F378% F2/F390% F2/F3 79% F2/F374% F2/F3 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Superior Effect in Type 2 Diabetes T2DM ≥ 1-stage improvement in Fibrosis qFibrosis - AI Overall Population ≥ 1-stage improvement in Fibrosis qFibrosis - AI 20.6% 34.3% 51.6% Placebo N=34 Icosa 300 mg N=35 Icosa 600 mg N=31 p=0.32 p=0.03 25.7% 34.3% 49.2% Placebo N=70 Icosa 300 mg N=67 Icosa 600 mg N=63 p=0.30 p=0.02 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Rapid, Sustained Effect on Markers of Liver Injury & Inflammation -20.0 -17.5 -15.0 -12.5 -10.0 -7.5 -5.0 -2.5 0.0 Change in AST (U/L) Weeks (U/L) Placebo 300 mg 600 mg 4 16 403224 LS means (95% CI) p-value vs placebo 0.004 0.019 -14.8 (-20.3, -9.4) -11.2 (-16.8, -5.6) -5.8 (-11.3, -0.3) 10 0.015 0.017 0.0210.0220.004 52 -30 -25 -20 -15 -10 -5 0 Change in ALT (U/L) Weeks (U/L) Placebo 300 mg 600 mg 4 16 403224 LS means (95% CI) p-value vs placebo <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.00080.0020 0.0080 0.00620.0003 <0.0001 -26.7 (-33, -22) -19.1 (-28, -10) -7.5 (-14, -1) -35 10 52 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Rapid, Sustained Effect on Markers of Liver Injury & Inflammation -30 -25 -20 -15 -10 -5 0 Change in GGT (U/L) Weeks (U/L) Placebo 300 mg 600 mg 4 16 403224 LS means (95% CI) p-value vs placebo <0.0001 0.0005 0.0006 0.0006 <0.0001 <0.0001 0.0055 0.02 0.0132 <0.0001 -26.7 (-37, -19) -23.8 (-33, -14.5) -5.6 (-14.8, 3.5) -35 10 -40 52 0.0009 0.0019 -25 -20 -15 -10 -5 0 5 Change in ALP (U/L) Weeks (U/L) Placebo 300 mg 600 mg 4 16 403224 LS means (95% CI) p-value vs placebo <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 -19.3 (-23, -16) -13.1 (-16.4, -9.9) 1.3 (-1.9, 4.5) 10 52 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Superior Reduction in ELF in Type 2 Diabetes T2DM Mean Change from Baseline in ELF Overall Population Mean Change from Baseline in ELF -0.01 -0.05 -0.29 Placebo N=70 Icosa 300 mg N=67 Icosa 600 mg N=63 p=0.02 -0.04 -0.06 -0.48 Placebo N=35 Icosa 300 mg N=40 Icosa 600 mg N=39 p=0.01 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Superior Reduction in ProC3 in Type 2 Diabetes T2DM Mean Change from Baseline in ProC3 Overall Population Mean Change from Baseline in ProC3 T2DM with baseline ProC3 ≥ 15.5 ng/mL* Mean Change from Baseline in ProC3 0.38 -3.35 -4.42 Placebo N=36 Icosa 300 mg N=31 Icosa 600 mg N=37 p=0.03 -0.77 -2.51 -3.41 Placebo N=75 Icosa 300 mg N=76 Icosa 600 mg N=75 p=0.04 -1.24 -6.88 -9.11 Placebo N=19 Icosa 300 mg N=21 Icosa 600 mg N=18 p=0.01 *15.5 ng/ml optimal PRO-C3 cut-off level for the detection of advanced fibrosis ≥F3(AUROC = 0.78) – Boyle et al, JHEP Rep 2019 Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Additional Benefits Overall Population Relative Change from Baseline in hsCRP versus Placebo T2DM with baseline HbA1c ≥6.5% Absolute Change from Baseline in HbA1c Overall Population Marked reductions (-30%, p<0.001) in LDL-C in subjects with elevated (>100 mg/dl) baseline levels No effect on body weight Non-significant reduction of Liver Fat Content 0.35 -0.75 -0.62 Placebo N=27 Icosa 300 mg N=27 Icosa 600 mg N=26 p<0.05 p<0.05 -59% -62% Icosa 300 mg N=76 Icosa 600 mg N=77 p<0.003 p<0.002 ~ 1% placebo-corrected reduction Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Favorable Safety/Tolerability Profile Percent of Subjects with Adverse Events (AEs) Placebo (n=91) Icosa 300 mg (n=92) Icosa 600 mg (n=95) Study Drug-Related TEAEs by Preferred Term (≥3% of Subjects) Nausea 1% 10% 13% Diarrhea 3% 4% 11% Constipation 3% 0% 0% Any TEAEs Leading to Study Drug Discontinuation 3% 2% 6% TEAEs Leading to Study Drug Discontinuation (GI disorders) 2.2% 0% 4.2% Nausea 1.1% 0% 2.1% Diarrhea 0% 0% 1.1% Dyspepsia 0% 0% 1.1% Eructation 1.1% 0% 0% Flatulence 1.1% 0% 1.1% Abdominal pain 1.1% 0% 0% Study Drug-Related Serious Adverse Events (SAEs) 0% 0% 0% • All Study Drug- Related Treatment Emergent Adverse Events (TEAEs) were mild or moderate in severity • There were no reports of DILI and no clinically significant changes in vital signs, physical exams results and ECGs • No difference between diabetics and total population Loomba R et al. J Lipid Res. 2015;56(1):185-92 Rationale for Superior Efficacy in T2DM with MASH Inflammation AA Cascade Lipotoxicity NASH Severity T2DM FFAR4 b-arrestin targeting FFAR1/4 Key Takeaways 2 1 • Icosabutate, an oral, once-daily, dual FFAR1/FFAR4 agonist did not meet its primary endpoint; however, it significantly improves MASH and fibrosis in T2DM as evidenced by: • Both conventional and AI pathology • Marked decreases in key biomarkers of liver damage, inflammation and fibrosis • Icosabutate was well-tolerated with mild to moderate TEAEs and no reports of DILI • This study provides rationale for further clinical development of icosabutate in diabetic NASH Slides are the property of the author and AASLD. Permission is required from both AASLD and the author for reuse. Thank you!

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