EASL International Liver Congress Paris, France 14 April 2018

Transcription

1 NGM282 Improves Fibrosis and NASH-Related Histology in 12 Weeks in Patients With Biopsy-Confirmed NASH, Which is Preceded By Significant Decreases in Hepatic Steatosis, Liver Transaminases and Fibrosis Markers at 6 Weeks Stephen A. Harrison, Stephen J. Rossi, Mustafa R. Bashir, Cynthia D. Guy, Rajarshi Banerjee, Mark J. Jaros, Sandra Owers, Bryan A. Baxter, Lei Ling, Alex M. DePaoli EASL International Liver Congress Paris, France 14 April 2018

2 Disclosures S. Harrison Speakers Bureau: Abbvie, Alexion: Consultant, Advisory Board: Echosens, Allergan, Perspectum, Prometheus, Galmed, Capulus, CiVi Biopharma, Corcept, Second Genome, Madrigal, Pfizer, NGM Bio, BMS, Gilead, Intercept, HistoIndex, Cirius, Axcella, Genfit, Novo Nordisk, Novartis, PPD, MedPace, IQVIA, Cymabay, Chronic Liver Disease Foundation: Grant/Research Support: Gilead, Intercept, Genfit, Cirius, NGM Bio, Galmed, Immuron, Galectin, Madrigal, Conatus, Allergan Stock: Madrigal, Cirius, Genfit, Metacrine R. Banerjee: Employee of Perspectum Diagnostics B. Baxter, A. DePaoli, L. Ling, S. Rossi: Employees of NGM Bio M. Bashir, C. Guy, M. Jaros, S. Owers: No disclosures April 14, 2018 [ 2 ]

3 NGM282 Targets Multiple Drivers of the Pathogenesis of NASH Biologic activity established in multiple preclinical models of NASH demonstrating improvements in NAS, fibrosis and markers of hepatic injury [ 3 ]

4 NGM282 is an Engineered Variant of Human FGF19 in Development for NASH NGM282 has been evaluated in > 400 subjects Completed Phase 2 studies in T2D, NASH, PBC and PSC Potent target engagement across all study populations A 12-week Phase 2 randomized, placebo-controlled trial of NGM282 (3 mg and 6 mg) in biopsy-confirmed NASH subjects demonstrated: 1 Significant reduction in liver fat content (LFC) by MRI-PDFF Rapid decreases in biomarkers relevant to resolution of NASH and improvement in fibrosis (ALT, AST, PRO-C3, ELF) No significant difference between 3 and 6 mg in overall efficacy Favorable safety and tolerability profile consistent with prior studies Data supported an exploratory 12-week study of NGM282 (3 mg) to assess the potential for early histologic changes on liver biopsy [ 4 ] 1 Harrison et al. Lancet 2018 Mar 24;391(10126):

5 Study Design and Key Enrollment Criteria SCREENING FOLLOW-UP NGM282 3 mg NGM282 3 mg Rosuvastatin (if needed) D-28 D1 W2 W4 W6 W8 W12 W18 MRI-PDFF LiverMultiScan TM Liver Biopsy MRI-PDFF LiverMultiScan TM MRI-PDFF LiverMultiScan TM Liver Biopsy MRI-PDFF LiverMultiScan TM Twenty-two subjects enrolled with biopsy-confirmed NASH at a single center NAS 4 (at least 1 point in each component) Stage 1-3 fibrosis LFC 8% (MRI-PDFF) Primary endpoint was a decrease in absolute LFC 5% at W12 Exploratory endpoint of change in liver histology at W12 Nineteen subjects completed 12 weeks of treatment with paired biopsies Rosuvastatin (ROS 20 mg) started at W2 if LDL-C rise of 10 mg/dl observed ROS dose titrated up to 40 mg at W4 to W8 if LDL-C remains above Baseline [ 5 ]

6 Baseline Demographics and Patient Characteristics Parameter (Mean value unless otherwise noted) [ 6 ] NGM282 3 mg (n=19) Male/Female 4/15 Age, Years (SD) 51.4 (12.6) Ethnicity (Non-Hispanic Latino/Hispanic Latino) 6/13 Type 2 Diabetes (Y/N) 7/12 Liver Fat Content, MRI-PDFF (SD) 17.1% (5.6) ALT, U/L (SD) 82 (39) AST, U/L (SD) 65 (32) 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, mg/dl (SD) 97 (27) Statin Naïve/Experienced 13/6 7α-hydroxyl-4-cholesten-3-one (C4), ng/ml (SD) 35.1 (24.2) Analysis includes 19 subjects that completed 12W of treatment with paired biopsies Three subjects were early withdrawals (all were unrelated to study drug): pleurisy, MVA, cardiac arrest (non-mi)

7 Suppression of C4 and Serum Bile Acids by NGM282 Reflects Potent Target Engagement C4 Levels Total Serum Bile Acids p < p < p < p < Mean C4 (ng/ml) Δ at W12 Mean (SD) Absolute (24.4) Relative -93% (10) Mean Total Bile Acids (μmol/l) Δ at W12 Mean (SD) Absolute -3.5 (2.5) Relative -64% (41) 0 Baseline C4 = 7α-hydroxyl-4-cholesten-3-one Lower Limit of C4 Quantitation = 0.9 ng/ml 0 W6 W12 Baseline W6 W12 (n=19) (n=19) [ 7 ]

8 Significant Decrease in Absolute and Relative LFC by MRI-PDFF After 6 and 12 Weeks of NGM % of subjects achieved primary endpoint of 5% absolute LFC reduction and a decreased relative LFC 30% at W12 12 (63%) of subjects normalized LFC (< 5%) by W12 20 p < p < Mean Absolute LFC (%) Δ at W12 Mean (SD) Absolute -11.2% (4.2) Relative -67% (17) 0 Baseline W6 (n=19) [ 8 ] W12

9 Rapid Decreases in Liver Transaminases Supportive of a Reduction in Inflammation Mean ALT/AST (U/L) ALT AST Δ at W12 ALT AST Absolute -53* -37* Relative -60%* -52%* 0 Baseline W2 W4 W6 W8 W10 W12 (n=19) * p < [ 9 ]

10 Fibrosis Markers are Significantly Reduced by NGM282 as Early as Week 6 PRO-C3 Levels ELF Score and Components Mean PRO-C3 (ng/ml) p < 0.05 p < 0.01 Δ at W12 Mean (SD) Absolute (18.4) Relative -33% (47) Mean (SD) Baseline W6 W12 ELF Score Hyaluronic Acid PIIINP TIMP (1.0) 91.4 (79.7) 13.4 (4.6) (67.7) 9.6* (0.8) 67.3 (60.2) 9.7* (3.5) 233.6* (51.4) 9.5* (1.0) 72.1 (90.3) 10.3* (3.4) 232.0* (62.5) *p < Baseline W6 W12 Subjects with severe disease (ELF > 10.1) decreased ELF Score by 0.8 at W12 [ 10 ]

11 Reduction in LIF and ct1 on Multi-Parametric MRI are Consistent with Other Non-Invasive Markers Correlation of LMS Parameters and Disease Severity LIF Score Mean Corrected T1 (ct1; ms) Severe Fibrosis > 3.0 > 950 Decreased Liver-Related Events < 2.0 < 875 No Fibrosis < 1.0 < 800 Mean (SD) Change in LIF Score and ct1 Baseline W6 W12 LIF (SD) 2.80 (0.43) 2.25 (0.52)* 2.05 (0.56)* ct1 (SD) 891 (56) 831 (56)* 812 (58)* *p < Baseline W6 W12 LMS = LiverMultiScanTM LIF = Liver Inflammation-Fibrosis 1 Banerjee et al, J Hepatol. 2014; 60(1): Data on file, Perspectum Diagnostics

12 Translation of Non-Invasive Efficacy into Histological Response at W12 Significant reductions across non-invasive parameters for NASH at W12 100% subjects had 5% absolute and 30% relative LFC reductions Mean ALT by 60% Exploratory fibrosis markers (PRO-C3, ELF) Conducted biopsy at Week 12 to assess the translation of early potent effects into changes in NASH-related histopathology and fibrosis Blinded biopsies at Baseline and Week 12 were pooled by an independent hepatopathologist at Duke University Liver biopsies performed within 3 months of screening and at W12 Scored using NASH CRN criteria (NAS, fibrosis) Biopsy samples were collected with a 16g needle; core length of > 15 mm with sufficient tissue and portal tracts for assessment [ 12 ]

13 Decrease Across All NASH Histological Parameters with NGM282 at W12 NAS HISTOLOGICAL RESPONSE AT W12 % of patients (n=19) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Mean change at W12 (SD) NAS Steatosis Inflammation Ballooning 84% (n=16) 74% (n=14) 42% (n=8) 53% (n=10) 53% 42% 11% 26% 5% 0% 5% 5% -2.3 (1.8) -1.1 (0.9) -0.5 (0.8) -0.7 (0.9) Improved No change Worsened [ 13 ]

14 Rapid Regression of Fibrosis at Week 12 in Patients Treated with NGM282 Fibrosis Stage at Baseline (% patients; n=19) Fibrosis Histologic Response at W12 Mean fibrosis stage = 2.5 F4 F1 5% 16% 42% (n=8) Improved F3 53% 26% F2 47% No change [ 14 ] 11% Worsened (1 point) Mean change from Baseline in fibrosis stage = -0.5 Three subjects had a 2-stage improvement in fibrosis: all F3 F1 Mean decrease in NAS in subjects with improved fibrosis = -3.5

15 NGM282 Potential to Impact Both Resolution of NASH and Fibrosis Improvement Endpoints Early Histologic Responders defined as subjects with: Reduction in NAS 2, with at least 1 point in inflammation or ballooning Reduction in fibrosis 1, with no worsening of NASH Resolution of NASH (inflammation = 0-1 and ballooning = 0) Early Histologic Responders = Δ NAS 2 (with Inflammation or Ballooning) Δ Fibrosis 1 Resolution of NASH 68% (n=13) 58% (n=11) 42% (n=8) 11% (n=2) [ 15 ]

16 NGM282 Histologic Response Aligns with Decreases Across Noninvasive Efficacy Markers BASELINE W6 W12 C4 (ng/ml) 12 < 0.9 < 0.9 LFC (MRI-PDFF) ALT (U/L) PRO-C3 (ng/ml) LIF H & E NAS = 8 H & E NAS = 4 Trichrome Stage 3 Fibrosis Trichrome Stage 1 Fibrosis [ 16 ]

17 Cholesterol Changes Effectively Managed with Statin Therapy 200 NGM282 3 mg NGM282 3 mg + Rosuvastatin (if needed, titration at W4, W8) 150 LDL-C (Mean, mg/dl) LDL-C levels return to baseline and/or target of 100 mg/dl with statin treatment Baseline W2 W4 W6 W8 W10 W12 Decreased C4 and increased LDL-C levels 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 [ 17 ]

18 Summary of NGM282 Safety and Tolerability Favorable safety and tolerability profile consistent with other NGM282 studies No new safety signals identified Mild GI 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 AEs GI symptoms were largely mitigated with separating the timing of injection around meals and decreasing meal size Three SAEs, all unrelated to study drug Pleurisy Chest tightness Cardiac arrest (non-mi) [ 18 ]

19 NGM282 Demonstrate Improvements Across Histological and Noninvasive Endpoints for NASH 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 % of patients demonstrated histological improvement at W12 68% of patients meet Early Histologic Responder criteria Unprecedented anti-fibrotic activity at W12 8 of 19 (42%) subjects (baseline F2/F3) had 1 fibrosis stage reduction 3 patients improved from F3 to F1 (2 stage improvement) Statin co-administration rapidly mitigates LDL-C elevations Majority of NGM282-treated patients reach LDL-C levels below baseline and/or achieve target within 4 weeks of initiating statin therapy Safe and well-tolerated consistent with other study populations Data supports advancing NGM282 to Ph2b study in NASH [ 19 ]