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GLP-1 receptor agonists for the treatment of MASH Arun J. Sanyal M.D. Z Reno Vlahcevic Professor of Medicine Director, Stravitz-Sanyal Institute for Liver Disease and Metabolic Health Virginia Commonwealth University School of Medicine Stravitz-Sanyal Institute for Liver Disease and Metabolic HealthFirst, I confess UNASHAMED LIVER LOVER I disclosethe following financialrelationship(s) with a commercial interest: • Ownership interests: Durect, Tiziana, Genfit, Exhalenz, Northsea, Rivus, Inversago • Consultant: Gilead, Intercept, Novartis,Novo Nordisk, Inventiva, Merck, Pfizer, Boehringer Ingelhiem, BristolMyers Squibb, Eli Lilly, Genentech, Amgen, Alnylam,Regeneron, Thera Technologies, Madrigal, Salix,Malinckrodt, Gatehouse, Rivus, Siemens, Lipocine, 89 Bio, Astra Zeneca, Akero, Foresite, Mitopower, Histoindex, Path AI, Takeda • Grantsupport to school: Gilead, Intercept, Novartis, Novo Nordisk, Inventiva, Eli Lilly, Genentech, BoehringerIngelhiem, Bristol MyersSquibb Stravitz-Sanyal Institute for Liver Disease and Metabolic Health The liver as a victim of the extrahepatic milieu (near universal recurrence post liver transplant) )100 e % recurrent f r n i NASH e y f t o r 50 l o b H recurrent b A fatty liver r N P o p= 0.003 logrank test 0 0 500 1000 1500 2000 time from OLT (days) FL/NASH 27/27 11/13 5/7 2/3 0/1 Contos et al, Liver Transplantation, 2001, 7: 363-373 SSLIatVCUThere is a strong rationale for therapies that attack multiple competing threats (CRM and liver) to life related to metabolic ill-health Diet-induced obesity Metabolic stress Systemic inflammation and fibrosis Arteries Heart Liver Pancreas Kidney (Hypertension, (HFPEF) (MASLD) (T2DM) (CKD) CVD,CAD, PVD) Competing threatsto life include MASLD/MASH, T2DM, hypertension, cardiac disease, vasculardisease, CKD diabetes mellitus, MASLD=metabolicdysfunction associated steatotic liver disease.sease;CVS, cardiovascular system; HFPEF, heart failurewith preserved ejection fraction;PVD, peripheral vascular disease; T2DM, type 2 SSLIatVCU Evolving obesity therapeutic landscape We are here! Single agonists (injectable) (e.g. semaglutide 2.4 mg, setmelanotide) Single agonists (oral) (e.g. oral semaglutide, orforglipron, danuglipron) Dual agonists (e.g. tirzepatide, survodutide, mazdutide, pemvidutide) Intensive First-generation Triple agonists lifestyle AOMs (e.g. retatrutide) therapy (e.g. phentermine, Combination therapies pnaltrexone/bupropion,, (e.g. CagriSema) orlistat, liraglutide 3 mg) New generation AOMs should have the ability : 1 • To safely produce an average of >10% placebo-subtracted weight loss in randomized clinical trials (i.e. over that attributable to lifestyle interventions) in the majority of patients or • To safely produce a ≥15% weight loss in over half the patients as an adjunct to lifestyle Having a wide range of therapeutic options enables treatments to be tailored to individual needs AOM,anti-obesity medication. 1. Garvey. J Clin Endocrinol Metab 2022;107:e1339. SSLIatVCUScope of talk • What is the impact of GLP-1 RA mediated weight loss on: • Steatosis • Steatohepatitis resolution • Fibrosis • Progression to cirrhosis • Stabilization of cirrhosis SSLIatVCU If weight is the problem, does weight loss solve the problem? Correlations betweenWLand Correlations* betweenWL and Weight loss fibrosisstatusatthe endof steatohepatitis resolution intervention Rho=0.55 ,p<0.01 Rho=0.13,p=0.02 18 18 ) 16 %16 10% fibrosis ( 12 s12 Fibrosis s 10 l10 t 8 h 8 7% steatohepatitis i 4 e 4 W 2 W 2 0 0 5% steatosis -4 -4 No Yes Worse Stable better Resolutionofsteatohepatitis Fibrosis status • Weightloss does notguaranteeNASHresolution • Fibrosisimprovementisnotasimple functionofweightloss alone Vilar Gomezet al,Gastroenterology. 2015 Aug;149(2):367-78Tackling MASLD burden of disease through its entire spectrum Cirrhosis (N= 1 million) NASH (MASH) Advanced fibrosis (F3/F4) (N=2 million) At risk NASH (MASH) NASH+ high activity + >=F2 fibrosis (N= 6-8 million) MASLD: fatty liver, steatohepatitis, fibrosis stages 0-1 Will a wipe out N= 60 million approx. of SLD avoid Main cause of death: cardiometabolic, cancers progression? SLD = SteatoticLiveAdapted from Estes et al, Hepatology 2018 SSLIatVCU GLP-1 receptor agonists have been transformational agents in the treatment of obesity and metabolic ill health Heart ↑Cardioprotection Kidneys ↑Natriuresis 0 ↑Diuresis Platelets s ↓Coagulation s l - 5 t Blood vessels g ↓Blood Intestine e GLP-1 ↓Postprandial w - 1 0 pressure lipids % - 1 5 Pancreas ) bo g) g) g) g) g Brain ↓Glucoseand ce 5m 1 m 2m 4m 0m ↓Bodyweight hypoglycaemia pla 0. (0. (. (. ( ↓Glucagon secretion a( a a a ir ↓Appetite ↑Insulin secretionand em em em em L ↓Satiety Fatand liver S S S S ↓Inflammation biosynthesis ↓Apoptosis O’Neilletal, Lancet.2018Aug25;392(10148):637-649. • FA, fatty acid; FFA, free fatty acid; GLP-1, glucagon-like peptide-1; TG, triglyceride. Wang XC et al. World J Gastroenterol 2014;20:14821–14830; Lee J et al. Diabetes Metab J 2012;36:262–267; Sharma S et al. PLoS One 2011;6:e25269. SSLIatVCUWeight loss can wipe out steatosis in early stages of disease *** 100 *** 89* 93 *** 86 80 79 e a60 *** 57* n 52 r e40 * 29* P 27 20 0 0 0 Week24 Week48 LiverFat Content <5% Sanyaletal, Nature Medicine, June 2024 Jastreboffetal, N Engl J Med 2023; 389:514-526 SSLIatVCURelationship of weight loss to loss of liver fat and loss of visceral adipose tissue Sanyaletal, Nature Medicine, June 2024 SSLIatVCUTackling MASLD burden of disease through its entire spectrum Cirrhosis (N= 1 million) NASH (MASH) Advanced fibrosis (F3/F4) Can weight loss (N=2 million) regress activity and fibrosis? At risk NASH (MASH) NASH+ high activity + >=F2 fibrosis (N= 6-8 million) MASLD: fatty liver, steatohepatitis, fibrosis stages 0-1 N= 60 million approx. Main cause of death: cardiometabolic, cancers SLD = SteatoticLiveAdapted from Estes et al, Hepatology 2018 SSLIatVCUWhat about MASH resolution? Courtesy David Kleiner, NASH CRN SSLIatVCUGLP-1 (semaglutide) and MASH resolution Newsomeetal, NEJM 2021; 384:1113-1124 SSLIatVCUWeight loss and MASH resolution- lessons from Tirzepatide Efficacy Estimand Overall population Overall baseline mean: 99.8±21.5 kg Baseline valuesare means ±SD.Data are Estimate; differencesversus placebo shown with 95% CI. The CIsare not adjusted for multiple comparisons and should not be used to inferdefinitive treatment effects. T2DM =type 2 diabetes mellitus;CI =confidence interval. Loomba etal, NEJM, 2024;391:299-310 SSLIatVCUMASH resolution by weight loss-data from SYNERGY ≥ 20% weight loss is needed for 90% + MASH resolution Loomba etal, NEJM, 2024;391:299-310 SSLIatVCUWeight loss and MASH resolution Verrastro etal, Lancet, 2023; 401:1786-1797 SSLIatVCUWeight loss and ballooning-data for semaglutide ~3-5% ~14% 74% 38% Newsomeetal, NEJM 2021; 384:1113-1124 SSLIatVCUWeight loss and lobular inflammation- data for semaglutide Newsomeetal, NEJM 2021; 384:1113-1124 SSLIatVCUWeight loss and NAFLD activity score Koutoukidiset al JAMA Intern Med.2019;179(9):1262-1271 SSLIatVCUImprovement in MASH with no worsening in fibrosis was observed in up to 83.0%* of participants that received survodutide (F1–F3 population) Paired biopsyresults* Alldata † P<0.0001 P=0.0010 100 100 ) P<0.0001 ) P<0.0001 ( 90 P<0.0001 ( 90 P<0.0001 t 80 t 80 a 83.0 a i 70 i 70 t 60 t 60 a 64.3 65.9 a 63.8 f 50 f 50 55.8 o 40 o 40 i i r 30 r 30 38.7 p 20 p 20 r r P 10 18.2 P 10 15.2 0 0 Survodutide, Survodutide, Survodutide, Placebo Survodutide, Survodutide, Survodutide, Placebo 2.4 mg 4.8 mg 6.0 mg (N=66) 2.4 mg 4.8 mg 6.0 mg (N=79) (N=56) (N=53) (N=44) (N=93) (N=69) (N=52) Actual treatment Survodutide isnotapprovedfor MASLD/MASH. ImprovementinMASHwasdefinedasNASreductionof ≥2pointswith≥1poin†decreaseinlobular inflammationor ballooning subscores.Noworseningoffibrosiswas definedasabsenceofanyincreaseinthefibrosisstage.P-vwithout endoftreatment biopsieswhowereconsideredasnon-responders. Errorbars represent95%confidenceintervals.ent. Alldatapertaintoparticipants Sanyaletal.NEJM 2024; doi:10.1056/NEJMoa2401755;Sanyal21 al.E21L 2024;presentationGS-006. SSLIatVCU © 2024 Boehringer Ingelheim International GmbH.All rights reserved.Weight loss and fibrosis-baseline stage matters! ~ 50% hadstage1 fibrosis Verrastro etal, Lancet, 2023; 401:1786-1797 SSLIatVCU Improvement in fibrogenic drive with retatrutide a,b Percent Change in Corrected SERUM Pro-C3 GEN1 Baseline mean estimate = 13.5 ug/L ■ Significant decreases in Pro-C3 with RETA vs. PBO (p<0.05): - *At 24 weeks for doses: ≥4 mg (range: -22.7% to -26.4%) - **At 48 weeks for doses: 1 mg, 4 mg, and 8 mg (range: -15.4% to -21.6%) * ** asterisksmarksignifibant differenndsforRETA vs.PBO with astignificance level of p<0.05. BL=baseline; ELISA=enzyme-linked immunosorbent assay; ID=initial dose; LS=leastsquares; PBO=placebo; Pro-C3=pro-peptide collagen III;RETA=retatrutide; SE=standard error.ure (correction factor =0.152). Sanyaletal, Nature Medicine, June 2024Weight loss and steatosis-lessons from Semaglutide ~3-5% ~14% Newsomeetal, NEJM 2021; 384:1113-1124 SSLIatVCUWeight loss and Fibrosis regression- lessons from Tirzepatide Overall population Overall baseline mean: 99.8±21.5 kg Baseline valuesare means ±SD.Data are Estimate; differencesversus placebo shown with 95% CI. The CIsare not adjusted for multiple comparisons and should not be used to inferdefinitive treatment effects. T2DM =type 2 diabetes mellitus;CI =confidence interval. Loomba etal, NEJM, 2024;391:299-310 SSLIatVCUWeight loss and Fibrosis regression- lessons from SYNERGY 20%orgreater weight loss is needed topullaway fromplaceboconvincinglyfor fibrosisimprovement Loomba etal, NEJM, 2024;391:299-310 SSLIatVCU Dual GCGR/GLP-1R agonists may affect the liver through two different pathways, unlike other dual GLP-1-based agonists GLP-1/GLP-1R 1,2 GCG/GCGR 1,2  Insulin secretion  Food intake  Energy expenditure (metabolic rate) Liver Pancreas GI tract Brain Adipose tissue Liver (indirect) (indirect) Steatosis Glucose- Gastric Food intake/ Lipolysis Fatty acid oxidation dependent emptying appetite(hypothalamic Glycogenolysis insulin secretion centers) Gluconeogenesis Lipolysis GCGR/GLP-1R dual agonism affects the liver through multiple direct and indirect mechanisms, and may offer improvements to people living with MASLD, MASH, and fibrosis 3,4 GCBoehringer Ingelheim, 2024. Survodutide phase II MASH results. Available at: https://www.boehringer-ingelheim.com/human-hea27h/metabolic-diseases/survodutide-top-line-results-mash-fibrosis; accessed June 2024.n 063; 4. SSLIatVCU © 2024 Boehringer Ingelheim International GmbH.All rights reserved.Improvement in liver fibrosis with no worsening in MASH was observed in up to 64.5%* of participants that received survodutide Paired biopsyresults(F1–F3)* Paired biopsyresults(F2/F3)* P=0.0006 P=0.0041 100 100 ) P=0.0055 ) P=0.1191 ( 90 P=0.0008 ( 90 P=0.0007 t 80 t 80 a a i 70 i 70 t 60 t 60 a a 64.5 f 50 f 50 56.1 o 40 50.0 50.0 o 40 i 45.3 i 40.9 r 30 r 30 p 20 p 20 r 21.2 r 25.9 P 10 P 10 0 0 Survodutide, Survodutide, Survodutide, Placebo Survodutide, Survodutide, Survodutide, Placebo 2.4 mg 4.8 mg 6.0 mg (n=66) 2.4 mg 4.8 mg 6.0 mg (n=54) (n=56) (n=53) (n=44) (n=41) (n=44) (n=31) Actual treatment inflammation,orsteatosis). P-valuesarenominal.*A sensitivityanalysis basedonparticipants withpairedbiopsyresultsat baselineandendoftreatment.Error barsrepresent 95%confidenceintervals.Sanyaletal. NEJM 2024; doi:10.1056/NEJMoa2401755;Sanyalet a28EASL28024;presentationGS-006. SSLIatVCU © 2024 Boehringer Ingelheim International GmbH.All rights reserved.Tackling MASLD burden of disease through its entire spectrum What about cirrhosis? Cirrhosis (N= 1 million) NASH (MASH) Advanced fibrosis (F3/F4) Multipletherapeuticoptions (N=2 million) • Resmetirom • GLP-1 based Rx At risk NASH (MASH) • Pioglitazone, vitaminE NASH+ high activity + >=F2 fibrosis (N= 6-8 million) MASLD: fatty liver, steatohepatitis, fibrosis stages 0-1 Rxunderlying obesityand N= 60 million approx. T2DM Main cause of death: cardiometabolic, cancers SLD = SteatoticLivAdapted from Estes et al, Hepatology 2018 SSLIatVCUWeight loss and fibrosis regression- lessons from Semaglutide cirrhosis trial Weight loss Fibrosisimprovement MASHresolution placebo Sema Loomba etal, Lancet Gastroenterol Hepatol, 2023; 6:511-522 SSLIatVCUWeight loss alone may not be sufficient to halt or regress advanced fibrosis Resolution of MASH according Evolution of fibrosisafter bariatric to weight loss2 surgery 2 P<0.001 P<0.001 100 100 90 ) ) ( 80 ( 80 i r l 70 60.0 c s s r 60 80.0 s 60 S 90.5 b A 50 F F2 MASH F3 MASH M n i 40 r40 w h g i n 30 e c a 20 Need to reduce e 20 40.0 n activity and fibrosis P r 10 20.0 9.5 P 0 Baseline 1 year 5 years 0 0–5 kg/m 5–10 kg/m >10kg/m2 0-5 kg/m2 5BMI loss2 >10 kg/m2 Brunt fibrosis score F0 F3 Resolution of MASH without F1 F4 worseningoffibrosis MASH and/or fibrosis worsening F2 • Lasailly et al. Gastroenterology 2020;159:1290. SSLIatVCUBariatric surgery in those with MASH and compensated cirrhosis may improve outcomes Aliet al,EASL2024, MS under review SSLIatVCUEffect of weight loss on hepatic decompensation events Table2. Numberof events in metabolicsurgerypatients and nonsurgical control patients in the unadjusted dataset beforeoverlapweighting a Total MetabolicSurgery Nonsurgical Controls (N=62) (N=106) OutcomeVariable Composite MALO(primaryendpoint) 52 10 42 b Encephalopathy 27 3 24 Ascites c 24 3 21 Varicealbleeding 6 0 6 Hepatocellularcarcinoma 8 2 6 Livertransplant 9 1 8 All-causemortality 32 6 26 Decompensation (secondaryendpoint) d 37 4 33 a After overlap weighting, asingleindividualno longerrepresentsa single dataentity,and thusrawcounts are notreported after overlap weighting. b Requiringtreatmentor hospitaladmission. c requiringdiuretictherapy,paracentesis,or transjugularintrahepaticportosystemicshunt; orcomplicationsof ascites including spontaneous bacterialperitonitis orhepato-pleural effusion. d Thesecondarycompositeendpointwas theprogression fromthecompensated cirrhosisto thedecompensated stage defined asthefirstoccurrenceofascites,variceal hemorrhage,or hepaticencephalopathy. MALO:major adverseliveroutcomes. AminianAlietal, EASL2024 SSLIatVCU A Phase 1 hepatic impairment trial assessed the safety, tolerability and PK of survodutide in patients with compensated/decompensated cirrhosis Absolute reductionsin MREfrombaselineto Week 28 Safety, tolerability and PKdata Baseline mean (kPa) 2.44 7.09 8.23 • Survodutide was generally tolerable in No cirrhosis (n=15) Child-Pugh A (n=10) Child-Pugh B (n=6) individuals with cirrhosis; gastrointestinal adverse eventsmost 0.0 common e ) g P -1.0 -0.13 -1.12 -1.02 • Survodutide had similar a ( pharmacokinetics in individualswith and c n withoutcirrhosis, including those with S e -2.0 decompensation + a n b • Treatmentwith survodutide was e m -3.0 associated with decreases in liver fat, M f stiffness and fibrosis markers, aswell as -4.0 improvementsin metabolic risk factors The safety profile, tolerability and PKof survodutide are acceptablefor patientsliving with compensated F4 cirrhosis presenting with varying degrees of hepatic impairment Survodutide is not approved for MASLD/MASH. Descriptive statistics of absolutechange in liver stiffness from baseline to week 28 by MRE (kPa) in the treated set (all participants who received≥1dose of survodutide) using on- and off-treatment data. MRE, magnetic resonance elastography; SD, standard devLawitz et al. EASL 202434presentation OS-119.sonance elastography; PK, pharmacokinetics. SSLIatVCU © 2024 Boehringer Ingelheim International GmbH.All rights reserved. Liver biology is likely to be determined by the differential changes in extrahepatic signals and state of the liver during weight loss ↓inflammatory-fibrogenic cytokines NAFL NASH F0-2 NASH F3 +HCC ↓metabolic substrate Proliferation/ Tumor e Altered - Glucose e Inflammation microbiomecues - Fattyacids a t ECM/ Fibrosis D ↓lipotoxic molecules 8 wks 22wks 52wks PPARα Signaling - Ceramides Sterol /FattyAcid Metabolism Cazanave etal, ScientificReports, Dec2017 ↑insulinsensitizers(adiponectin) AMPK activation SSLIatVCUScope of talk • What is the impact of GLP-1 RA mediated weight loss on: • Steatosis- NEED ≥ 20% • Steatohepatitis resolution- NEED ≥ 20% • Fibrosis- NEED ≥ 20% • Progression to cirrhosis- NEED MORE DATA • Stabilization of cirrhosis- NEED ≥ 20% SSLIatVCUSSLIatVCU THANKYOU Stravitz-Sanyal InstituteforLiverDisease and Metabolic Health VCU