NGM282 in NASH: Phase 2 Study on Liver Fat Reduction and Histology Changes

A phase 2 study on NGM282 in NASH patients showed a significant decrease in liver fat content, meeting the primary endpoint. Exploratory findings also indicated potential improvements in liver histology. The treatment involved NGM282 at 3 mg QD, with additional rosuvastatin if needed. Promising results were observed in liver biopsies, MRI-PDFF measurements, and NAFLD activity scores, highlighting the potential of NGM282 in treating NASH. Fibrosis markers also showed positive trends, suggesting a comprehensive impact on liver health.

• NASH treatment
• NGM282
• liver fat reduction
• histology changes
• phase 2 study

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1. NGM282 in NASH: 3 mg QD (phase 2) Design W2 W12 Liver biopsy with NASH NAS * 4 with a score 1 for each component Stage 1-3 of fibrosis Liver fat content 8% (MRI-PDFF) NGM282 3 mg + rosuvastatin (if needed) NGM282 3 mg N = 19 Screening X X X W6 - X X W12 X X X W18 - X X Assessments Liver Biopsy MDRI-PDFF LiverMultiScan * NAFLD Activity Score: steatosis (0 to 3), lobular inflammation (0 to 3), ballooning (0 to 2) NGM282: engineered variant of human FGF19, administered subcutaneously qd Rosuvastatin: started at W2 if LDL-cholesterol rise of 10 mg/dl observed Endpoints Primary: decrease in absolute liver fat content 5% at W12 Exploratory: change in liver histology at W12 Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

2. NGM282 in NASH: 3 mg QD (phase 2) Baseline characteristics, mean or N or % NGM282 3 mg N = 19 Age, years (SD) 51.4 (12.6) Male / Female, N 4/15 Diabetes mellitus, N 7/12 Liver fat content, MRI-PDFF (proton density fat fraction), % (SD) 17.1% (5.6) AST, U/l (SD) 65 (32) ALT, U/l (SD) 82 (39) Fibrosis stage (SD) 2.5 (0.8) NAFLD activity score (SD) 5.7 (1.5) Liver-Inflammation-Fibrosis (LIF) score (SD) 2.80 (0.43) LDL cholesterol, mg/dL (SD) 97 (27) Statin na ve/experienced 13/6 7 -hydroxyl-4-cholesten-3-one (C4), ng/ml (SD) 35.1 (24.2) Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

3. NGM282 in NASH: 3 mg QD (phase 2) Effect on FGF19 targets (N = 19) Mean C4 levels, ng/mL Mean Total serum bile acids, mol/L p < 0.0001 p < 0.0001 40 6 p < 0.0001 p < 0.0001 35 5 at W12 Mean (SD) at W12 Mean (SD) 30 -33.2 (24.4) -3.5 (2.5) Absolute Absolute 4 25 -93% (10) -64% (41) Relative Relative 3 20 15 2 10 1 5 0 0 Baseline W6 W12 Baseline W6 W12 C4 = 7 -hydroxyl-4-cholesten-3-one Lower limit of C4 quantitation = 0.9 ng/ml Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

4. NGM282 in NASH: 3 mg QD (phase 2) Primary endpoint: mean % absolute change in liver fat content at W12 (N = 19) p < 0.0001 20 p < 0.0001 at W12 Mean (SD) 15 -11.2% (4.2) -67% (17) Absolute Relative 10 5 0 Baseline W6 W12 100% of subjects achieved primary endpoint of 5% absolute liver fat content reduction and a decreased of relative liver fat content 30% at W12 12 (63%) subjects normalized liver fat content ( 5%) by W12 Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

5. NGM282 in NASH: 3 mg QD (phase 2) Fibrosis markers changes at W12, N = 19 Mean PRO-C3 levels (ng/mL) ELF Score and components p < 0.05 6 p < 0.01 Mean (SD) Baseline W6 W12 10.1 (1.0) 9.6* (0.8) 9.5* (1.0) ELF score 5 at W12 Mean (SD) 91.4 (79.7) 67.3 (60.2) 72.1 (90.3) -11.1 (18.4) Absolute Hyaluronic acid 4 -33% (47) Relative 13.4 (4.6) 9.7* (3.5) 10.3* (3.4) PIIINP 3 270.8 (67.7) 233.6* (51.4) 232.0* (62.5) TIMP-1 2 *p < 0.01 1 Subjects with severe disease (ELF 10.1) decreased ELF score by 0.8 at W12 0 Baseline W6 W12 Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

6. NGM282 in NASH: 3 mg QD (phase 2) NAS histological response at W12, N = 19 % NAS Steatosis Inflammation Ballooning 100 90 80 42% 53% Improved 70 74% 60 84% 50 40 53% 30 42% No change 20 26% 11% 5% 10 0% Worsened 5% 5% 0 Mean change at W12 (SD) -2.3 (1.8) -1.1 (0.9) -0.5 (0.8) -0.7 (0.9) Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

7. NGM282 in NASH: 3 mg QD (phase 2) Fibrosis evolution at W12 (liver biopsy), N = 19 42% Improved 47% No change 11% Worsened Mean change from baseline in fibrosis stage: - 0.5 3 subjects had a 2-stage improvement in fibrosis: all F3 changed for F1 Mean decrease in NAS in subjects with improved fibrosis: -3.5 Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

8. NGM282 in NASH: 3 mg QD (phase 2) Mean transaminases (U/L), N = 19 100 at W12 ALT AST 90 ALT Absolute Relative -53* -60%* -37* -52%* 80 70 60 *p < 0.0001 50 AST 40 30 20 10 0 Baseline W2 W4 W6 W8 W10 W12 Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

9. NGM282 in NASH: 3 mg QD (phase 2) LDL-cholesterol (mg/dL) changes during treatment NGM282 3 mg NGM282 3 mg Rosuvastatin (if needed) 200 150 100 50 LDL-C levels return to baseline and/or target of < 100 mg/dL with statin treatment 0 Baseline W2 W4 W6 W8 W10 W12 Decreased C4 and increased LDL-cholesterol reflect potent CYP7A1 inhibition Lipid particle change primarily driven by increase in large LDL particles Significant reductions in serum triglycerides (56%) and no change in HDL Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

10. NGM282 in NASH: 3 mg QD (phase 2) Safety and tolerability Favorable safety and tolerability profile consistent with other NGM282 studies (no new safety signals identified) Mild gastrointestinal symptoms (loose/frequent stools) remain the most common treatment emergent adverse events Majority were mild and resolved during treatment phase No subject withdrew from treatment due to any drug-related adverse events Gastrointestinal symptoms were largely mitigated with separating the timing of injection around meals and decreasing meal size Three severe adverse events, all unrelated to study drug: Pleurisy Chest tightness Cardiac arrest (non myocardial infarction) Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2

11. NGM282 in NASH: 3 mg QD (phase 2) Summary Potent C4 and bile acid suppression consistent with FGF19 hormone activity Significant and clinically meaningful reductions across non-invasive markers of NASH-related disease Large percentage of patients demonstrated histological improvement at W12 Statin co-administration rapidly mitigates LDL-cholesterol elevations Treatment was safe and well tolerated Harrison SA, EASL 2018, Abs. GS-014 NGM282-Phase 2