2024-07-01 Journal-finalGLP-1 obesity .pptx

GLP-1 obesity

1. 報告者 : R3 韓逸宏 指導老師：陳錫榮醫師 2024/07/01

2. Study Overview 1 st end point: MASH (Reduction) 2nd end points: Liver fat content (Reduction), Fibrosis (Reduction) QW for 48 weeks MASH Placebo Survodutide 2.4mg 4.8mg 6.0mg Metabolic dysfunction-associated steatohepatitis

3. Front. Med., 27 November 2023, Volume 10 - 2023 Introduction: Increasing burden of the disease worldwide, 35 million

4. Introduction: Before 2024, weight loss, exercise, diet control were the only measures for MASH March 2024, Resmetirom (selective thyroid hormone receptor beta agonist) -> 1 st FDA approved med for MASH fibrosis -> Only 10.2~ 11.8% improvement Compound in development for MASH: GLP-1 (glucagon-like peptide-1) receptor agonist -> Obesity -> Risk factor -> Hepatocytes lack GLP-1 receptor (indirect) -> Medication with Hepatic and Extra-hepatic effects

5. Diabetes Research and Clinical Practice, Volume 207, January 2024, 110779 Introduction: (G lucagon receptor) (Glucagon-like peptide-1)

6. Survodutide mechanism of action at target organs Nature Metabolism | VOL 2 | May 2020 | 413–431 GLP-1R GLP-1R GCGR GLP-1/ GCG Dual-Agonist Survodutide

7. 1 st end point: MASH (Reduction) 2nd end points: Liver fat content (Reduction), Fibrosis (Reduction) Safety and adverse effects QW for 48 weeks Placebo Survodutide 2.4mg 4.8mg 6.0mg Methods: Phase 2 International Double-blind Randomized Key inclusion criteria: 18-80 yrs MASH (Biopsy) NAFLD score: ≥ 4 (0-8) Fibrosis stage: F1,F2,F3 MRI-PDFF: Fat >8% 1:1:1:1

8. NAFLD activity score (NAS) : ( 脂肪變性 ) ( 肝小夜發炎 ) ( 肝細胞氣球狀變性 )

9. Fibrosis stage: Int. J. Mol. Sci.   2020 ,  21 (11), 4039

10. Figure 5: Chemical shift–encoded (CSE) MRI enables simultaneous estimation of both liver fat and iron deposition. Fat-corrected R2* (R2* = 1/T2*) mapping is a natural byproduct of multi-echo CSE acquisitions used for R2*-corrected proton density fat fraction (PDFF) mapping. Shown are representative MRI scans in three patients with various fat and iron levels throughout the liver. Starekova J. Published Online: September 21, 2021 https://doi.org/10.1148/radiol.2021204288 MRI-PDFF Magnetic Resonance Imaging (Proton Density Fat Fraction) N on-invasive, quantitative biomarker to assess liver fat content

11. 1 st end point: MASH (Reduction) 2nd end points: Liver fat content (Reduction), Fibrosis (Reduction) Safety and adverse effects QW for 48 weeks Placebo Survodutide 2.4mg 4.8mg 6.0mg Methods: Phase 2 International Double-blind Randomized Key inclusion criteria: 18-80 yrs MASH (Biopsy) NAFLD score: ≥ 4 (0-8) Fibrosis stage: F1,F2,F3 MRI-PDFF: Fat >8% Key exclusion criteria: Significant EtOH use Other forms of chronic liver disease 1:1:1:1

12. Methods: Participant flow n = 295 1153 enrolled

13. Method: Study Design

14. Method: Dose Escalation Escalation ( 劑量上調 ) Maintenance ( 劑量維持 )

15. Results : Demographic and Clinical Baseline

16. Results : Demographic and Clinical Baseline

17. Results : Primary End Point after 48 Week MASH (NAFLD score Reduction at least 2 points ) No worsen fibrosis stage (P<0.001)

18. Results : Secondary End Point after 48 Week

19. Results : Secondary End Point after 48 Week

20. Results : Change in Liver-Enzyme Levels over Time. (ALT) (AST)

21. Results : Adverse effects GI

22. Results : Adverse effects

23. QW for 48 weeks Placebo Survodutide 2.4mg 4.8mg 6.0mg Summary: Phase 2 International Double-blind Randomized 1:1:1:1 MASH GI adverse effects GCG/GLP-1

24. Discussion I: Benefit of Dual GCG+GLP-1 In this phase 2 trial, Survodutide was associated with significant improvement in MASH with no worsening of fibrosis (P<0.001). Also benefit in fibrosis (34% vs. 22% placebo) Dual GCG + GLP- 1 agonist > Mono GLP-1 agonist for MASH Direct hepatic effect through glucagon receptor agonism + extrahepatic effects through GLP-1 receptor agonism. In a phase 2 trial, treatment with the GLP-1 receptor monoagonist Semaglutide resulted in MASH reduction but not fibrosis stage . The benefit of Survodutide with respect to fibrosis will need to be examined in future studies.

25. Discussion II: GCG+GLP-1 ratio Cotadutide , Dual GCG + GLP- 1 agonist: 1:5, improved the NAFLD fibrosis score and levels of ALT, AST A phase 2 trial of SAR425899, was halted owing to a high incidence of GI adverse events NNC9204-1177, Dual GCG + GLP- 1 agonist: 1:3 , was stopped owing to a dose-dependent increase in heart rate , a decrease in the reticulocyte count , and increased markers of inflammation . Survodutide , Dual GCG + GLP- 1 agonist: 1:8 . Our findings suggest that an appropriate ratio may achieve a beneficial effect of glucagon receptor–GLP-1 receptor dual agonism in patients with MASH, with a potentially acceptable adverse-event profile.

26. Discussion III: Survodutide Safety and limitations Adverse-Event Profile: Similar to previous phase 2 trial involving obesity. Common adverse events: nausea, vomiting, diarrhea. Discontinuation Rates: Survodutide : 20% V.S Placebo: 3%. Higher discontinuation during rapid dose-escalation . Suggest slower dose-escalation to mitigate discontinuation. Safety Issues: No unexpected safety issues identified. Trial Limitation: Majority of participants were White. May limit generalizability. Conclusion: Supports potential of Survodutide for MASH and liver fibrosis. Further investigation in phase 3 trials warranted.

27. Thank you~~

28. Results : Primary End Point after 48 Week Improvement: NAFLD score reduction ≥ 2 (P<0.001)

29. Fibrosis stage: Clinical and Experimental Medicine (2023) 23:273–285

30. Discussion III: The adverse-event profile of survodutide was similar to that in a previous phase 2 trial involving participants living with obesity, in which the most common adverse events were nausea, vomiting, and diarrhea. In our trial, the discontinuation of survodutide and placebo because of adverse events occurred in 20% and 3% of the participants, respectively. Discontinuation of survodutide mainly occurred during the rapid dose-escalation phase of the trial and may be mitigated by a slower dose-escalation approach. Furthermore, no unexpected safety issues were identified. A limitation of this trial was that most participants were White, which may restrict the generalizability of the findings. The results of this phase 2 trial support the potential for survodutide as a treatment for patients with MASH and liver fibrosis. These results warrant further investigation of this compound in phase 3 trials.

31. The Emerging Role of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis   Layla A. Abushamat, Pir Ahmad Shah, Robert H. Eckel, Stephen A. Harrison, Diana Barb   Clinical Gastroenterology and Hepatology   DOI: 10.1016/j.cgh.2024.01.032 Copyright © 2024 AGA Institute Terms and Conditions

32. Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032)

33. Figure 1 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

34. Figure 2 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

35. Figure 3 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

36. Figure 4 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

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42. Front. Med., 27 November 2023, Volume 10 - 2023

43. Front. Med., 27 November 2023, Volume 10 - 2023

44. Summary of Survodutide mechanism of action at target organs Nature Metabolism | VOL 2 | May 2020 | 413–431

45. Diabetes Research and Clinical Practice, Volume 207, January 2024, 110779

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