Comprehensive Case Challenges in MASH

Learning Objectives •Identify noninvasive tools that optimize diagnosis, staging, and monitoring of MASH •Develop treatment plans that incorporate recently approved and available therapies that target MASH and comorbid metabolic conditions •Describe recent advances and ongoing research in MASH diagnostics and pharmacologic treatment options

MASH, metabolic dysfunction-associated steatohepatitis.

MANAGING ADVANCED FIBROSIS IN PATIENTS WITH MASH

Case 1: Cristina • 73-year-old Latina woman • BMI, 26 kg/m2 • ALT, 60 U/L; AST, 45 U/L • TE, 12 kPa • FIB-4 score, 2.0 • LDL-C, 120 mg/dL; BP, 135/80 mm Hg • Family history of cirrhosis • Not currently taking any medications or have any comorbidities • Abnormal liver enzymes documented for the past 3 years ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; FIB-4, Fibrosis-4; LDL-C, low-density lipoprotein cholesterol; TE, transient elastography.

Benefits of Early Treatment Initiation All-Cause Mortality

Liver-Related Mortality 45

10 9 8 7 6 5 4 3 2 1 0

Mortality Rate Ratio

Mortality Rate Ratio (95% CI)

Liver Fibrosis Associated With Mortality

6.4

3.48 2.52 1.58 0

1

2

3

4

Fibrosis Stage Mortality Rate per 1000 PYF 15.2 17.1

27.9

PYF, person-years of follow-up.

Dulai PS, et al. Hepatology. 2017;65(5):1557-1565.

42.3

40 35 30 25 16.69

20 15

9.57

10 1.41

5 0 0

1

2

3

4

7.92

23.3

Fibrosis Stage 36.0

45.8

Mortality Rate, per 1000 PYF 0.30 0.64

4.28

Patient Eligibility for Resmetirom Resmetirom was approved by the FDA for the treatment of MASH in 2024. 1

Step 12,3

Step 2

Confirm MASLD and exclude other causes of liver disease

Identify patients with confirmed or likely F2 or F3 for treatment

Step 3 AND

Exclude cirrhosis

MASH with F2 or F3

Cirrhosis on biopsy

OR

OR

• TE, 8-15 kPa • MRE, 3.1-4.4 kPa • ELF score, 9.2-9.7 (+ second NIT) • ELF score, 9.8-11.3 (if in isolation) • FAST, MAST, MEFIB

Consider treatment with resmetirom

• TE, ≥20 kPa; MRE, ≥5 kPa; ELF score, >11.3 • Platelets, ≤140,000/μL • Evidence of PHTN, active thyroid disease or concomitant acute liver disease • Excess alcohol use

F, fibrosis stage; FAST, FibroScan-AST; MASLD, metabolic dysfunction-associated steatotic liver disease; MAST, magnetic resonance imaging-AST; MEFIB, MRE and FIB-4; MRE, magnetic resonance elastography; PHTN, portal hypertension; US Food and Drug Administration (FDA).

1. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217785s000lbl.pdf; 2. Noureddin M, et al. Clin Gastroenterol Hepatol. 2024;22(12):2367-2377; 3. Chen VL, et al. Hepatology. 2025;81(1):312-320.

Head-to-Head Comparison of Composite Biomarkers for Detecting At-Risk MASH Original cutoffs

100

FAST

MAST

MEFIB

FNI

Patients, %

80

AUROC 0.68

0.74

Adapted cutoffs

0.79a

0.81a

69a

60

56b

40 39

40

48

46 38b

20

Fibrotic MASH NAS ≥4 + ≥F2 (centrally reviewed)

0 FNI

MEFIB

MAST

Should cut-offs be adapted to T2D? aP=0.01; bP<0.001.

N=245 patients with T2D and suspected MASLD from the QUID-NASH study underwent TE, MRE, MRI-PDFF, routine laboratory tests, and liver biopsy.

AUROC, area under the receive operating characteristic; FNI, fibrotic NASH index; MRI-PDFF, MRI-PDFF, magnetic resonance imaging-derived proton density fat fraction; T2D, type 2 diabetes.

Castera L, et al. J Hepatol. 2024;81:195-206.

FAST

Exploring Emerging NITs Score FAST1,2

Components TE + AST

Cutoff

Notes

≥0.67

Predictivity is largely driven by AST, and this cutoff may fail to identify many patients

MAST1,3

MRI + AST

≥0.242

If MRE is 4.4–4.9, additional caution needed to exclude the presence of cirrhosis

MEFIB1,4

MRE + FIB-4

FIB-4 1.6 plus LSM by MRE, 3.3 kPa

Positive MEFIB has a high PPV of >90%

NIS2+5

miR-34a-5p + YKL-40

≥0.6815

Corrects for sex for miR-34a-5p values

LSM, liver stiffness measure; PPV, positive predictive value.

1. Noureddin M, et al. Clin Gastroenterol Hepatol. 2024:S1542-3565(24)00667-0; 2. Newsome PN, et al. Lancet Gastroenterol Hepatol. 2020;5(4):362-373; 3. Noureddin M, et al. J Hepatol. 2022;76(4):781-787; 4. Ajmera V, et al. Therap Adv Gastroenterol. 2022;15:17562848221093869; 5. Harrison SA, et al. J Hepatol. 2023;79(3):758-767.

Assessing Safety and Efficacy of Resmetirom Assess Safety and Efficacy No response Start resmetirom • 80 mg if <100 kg • 100 mg if >100 kg

Confirm safety • Routine DILI parameters • Tolerability

3 Months DILI, drug-induced liver injury.

Chen VL, et al. Hepatology. 2025;81(1):312-320.

• Worsening of NITs • Consistent increase in ALT

Treatment monitoring, including safety (thyroid function, lipid profile)

6 Months

Benefit uncertain • TE <25% or MRE <20% drop in LSM • ALT: no significant improvement • MRI-PDFF: <30 reduction

Stop Consider continuing, addon, or alternate approach

Beneficial response • ALT: significant improvement or normalization • TE: ≥25% or MRE: ≥20% drop in LSM

12 Months

Continue

Case 1 Continuation • Had PNPLA3 test performed – GG phenotype

ALT, alanine aminotransferase; BMI, body mass index; FIB-4, Fibrosis-4 score; TE, transient elastography.

Role of PNPLA3 in MASH and Its Heritability • Conflicting data about relationship between PNPLA3 and occurrence of cardiometabolic conditions and outcomes1 – Some evidence that it is protective against T2D – Association with a prothrombotic status

• Improvements seen with tirzepatide across all 3 PNPLA3 phenotypes2 – MASH resolution greater for CC genotype vs G-allele carriers – Fibrosis improvement similar across genotypes

• Genetic risk scores can help predict fibrosis progression and cirrhosis development3 • PNPLA3 risk alleles did not affect response to resmetirom4 • Therapies targeting PNPLA3 are currently in development3 HCC, hepatocellular carcinoma; T2D, type 2 diabetes.

1. Petta S, et al. Liver Int. 2024. [Epub ahead of print]; 2. Sanyal A, et al. AASLD. November 15-19, 2024; San Diego, CA. Abstract 5014; 3. Tulone A, et al. United European Gastroenterol J. 2024;12(5):638-648; 4. Chalasani N, et al. AASLD. November 15-19, 2024; San Diego, CA. Abstract 0004.

MASH Therapies in Phase 3 Trials Drug

Trial Name

Population

Resmetirom Semaglutide Lanifibranor Efruxifermin

MAESTRO-NASH ESSENCE NATiV3

MASH with F1b, F2, or F3 MASH with F2 or F3 MASH with F2 or F3 Compensated cirrhosis due to MASH Noninvasively diagnosed MASH or MASLD MASH with F2 or F3 Compensated cirrhosis due to MASH MASH with F2 or F3 Mash with F2 or F3 MASLD and MASH MASH with cirrhosis MASH with F2 or F3

Pegozafermin Denifanstat Survodutide

ENLIGHTEN-Fibrosis FASCINATE-3 FASCINIT LIVERAGE - Cirrhosis LIVERAGE

National Library of Medicine. www.clinicaltrials.gov.

MANAGING MASH AND ITS METABOLIC COMORBIDITIES

Case 2: Richard • 68-year-old White man • BMI, 35 kg/m2 • 7-year history of T2D; HbA1c, 8.1% • eGFR, 57 mL/min/1.73 m2 • ALT, 72 U/L; AST, 65 U/L; GGT, 119 U/L • 9-year history of obstructive sleep apnea • LDL-C, 85 mg/dL • Liver biopsy 2 years ago, F2 • Has received vitamin E in the past but no effect on his AST or ALT • Currently taking atorvastatin and metformin HbA1c, glycated hemoglobin; eGFR, estimated glomerular filtration rate.

Effect of GLP-1 RAs on MACE

10

Tirzepatide Predicted to Reduce Future CVD Events2,b 12

Placebo

10.14

Semaglutide

10

c

8 6 4 % RELATIVE RISK

20 REDUCTION

2

% RELATIVE RISK

24 REDUCTION 7.75

8

Risk, %

Cumulative Incidence, %

Semaglutide Reduced MACE in Adults With Obesity and CVD1,a

6 4

2 0

0

6

12

18

24

30

Months

36

42

48

0 CVD pretreatment risk

CVD posttreatment risk

aN=17,604 adults aged ≥45 years with BMI ≥27 kg/m2 and established CVD but no history of T2D were randomly assigned 1:1 to weekly SQ semaglutide 2.4 mg or placebo; bN=4015

adults were identified in US NHANES as eligible for tirzepatide. The estimated 10-year CVD risks were calculated based on Framingham CVD risk scores.; cP<0.001.

CVD, cardiovascular disease; MACE, major adverse cardiovascular event; NHANES, National Health and Nutrition Examination Survey; SQ, subcutaneous.

1. Lincoff AM, et al. N Engl J Med. 2023;389(24):2221-2232; 2. Wong ND, et al. Cardiovasc Drugs Ther. 2024. [Epub ahead of print]

Efficacy of GLP-1 RAs in Patients With Obesity Tirzepatide Significantly Reduced Body Weight at Week 722,b

0 -2 -4 -6 -8 -10 -12 -14 -16 -18

c

Placebo Semaglutide 2.4 mg 0 4 8 12 16 20

28

36

44

52

60

Weeks Since Randomization

68

Change in Body Weight, %

Change From Baseline, %

Semaglutide Significantly Reduced Body Weight at Week 681,a

0

Overall mean baseline weight=104.8 kg

-2.4

-4

-3.1

-8 -12 -16 -20 -24

Placebo Tirzepatide 5 mg Tirzepatide 10 mg Tirzepatide 15 mg 0 4 8 12162024

36

-16.0 -21.4 -22.5 48

60

72

c

-15.0

c c

-19.5 -20.9

TRE

Weeks Since Randomization

aN=1961 adults with BMI ≥30 kg/m2 or ≥27 kg/m2 with weight-related comorbidities who do not have T2D were randomly assigned 2:1 to weekly SQ semaglutide 2.4 mg or placebo for 68

weeks; bN=2539 adults with BMI ≥30 kg/m2 or ≥27 kg/m2 with weight-related comorbidities who do not have T2D were randomly assigned 1:1:1:1 to SQ tirzepatide 5mg, 10mg, or 15 mg, or placebo for 72 weeks; cP<0.001 vs placebo.

TRE, treatment-regimen estimand.

1. Wilding JPH, et al. N Engl J Med. 2021;384(11):989-1002; 2. Jastreboff AM, et al. N Engl J Med. 2022;387(3):205-216.

Efficacy of Semaglutide in MASH ESSENCE Trial Semaglutide Improved Multiple MASH Measures at 72 Weeks 80

Placebo

Patients, %

70

Semaglutide 2.4 mg 62.9a

60 50 40

37 a

34.1

30

32.8a

22.5

16.2

20 10 0 Resolution of MASH with no worsening of fibrosis

Improvement in fibrosis with no Combined resolution of MASH with worsening of MASH improvement in fibrosis

Improvements were also seen in weight and cardiometabolic parameters.

N=1200 patients with biopsy-defined MASH and F2/F3 were randomly assigned 2:1 to weekly semaglutide 2.4 mg SQ or placebo for 240 weeks. The first 800 patients were included in the interim analysis at 72 weeks. aP<0.0001.

Newsome P, et al. American Association for the Study of Liver Diseases annual meeting. San Diego, California; November 15-29, 2024. Abstract 5018.

Efficacy of a Dual GIP/GLP-1 RA in MASH SYNERGY-NASH Trial Tirzepatide Showed Higher Rates of MASH Resolution at 52 Weeks 80 70

Patients, %

60

Placebo Tirzepatide 5 mg Tirzepatide 10 mg Tirzepatide 15 mg

50

62a 56a

55

51

51

44a

40 30

30 20 10

10 0

Resolution of MASH with no worsening of fibrosis aP<0.001 vs placebo.

Decrease of ≥1 fibrosis stage and no worsening of MASH

N=190 patients with biopsy-confirmed MASH and F2 or F3 were randomly assigned to weekly SQ tirzepatide 5 mg, 10 mg, or 15 mg, or placebo for 52 weeks.

GIP, gastric inhibitory polypeptide.

Loomba R, et al. N Engl J Med. 2024;391(4):299-310.

Effect of Bariatric Surgery on Fibrosis in Patients With MASH Improvement in Fibrosis Following Bariatric Surgery Among Patients With Advanced Fibrosis 100 28

80

F1

19

F2

70

F3

60

28

F4

50

40

0

F0

8 72

30

19

20 25

10

-5

-10

Baseline

1 Year

Baseline

End of Follow-Up

Histological responders (n=47) Normal liver (n=19) Fibrosis nonresponders (n=17)

-15 -20 -25

a

-30 a

-35

0 aP<0.01.

Change in BMI, %

Patients, %

90

Bariatric Surgery Resulted in Improved Liver Histology

Follow-up

N=196 patients with advanced MASH underwent bariatric surgery. N=66 had a follow-up liver biopsy at 3 years, with 36 showing advanced fibrosis.

Pais R, et al. Hepatology. 2022;76(2):456-468.

a

The Future of Therapies to Target MASH and Cardiometabolic Comorbidities • Semaglutide + cilofexor/firsocostat1 – Phase 2 trial showed combination was well tolerated, with greater improvement in steatosis, fibrosis, and liver biochemistry vs semaglutide monotherapy •Weight loss similar to semaglutide monotherapy

• Survodutide2,3 – Phase 2 trial showed greater rates of improvement in MASH, reduced liver fat, and improvement in fibrosis by ≥1 stage vs placebo – Ongoing phase 3 trials – Breakthrough therapy designation for noncirrhotic MASH

• Semaglutide + zalfermin4 – Phase 2 trial ongoing in patients with MASH and F2-F4 1. Alkhouri N, et al. J Hepatol. 2022;77(3):607-618; 2. Sanyal A, et al. N Engl J Med. 2024;391(4):311-319; 3. Boehringer Ingelheim. https://www.boehringer-ingelheim.com/humanhealth/metabolic-diseases/survodutide-us-fda-breakthrough-therapy-phase-3-trials-mash; 4. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05016882.

Conclusions • Resmetirom is the first FDA-approved therapy for MASH – Eligible patients have MASH with F2/F3

• In addition to established NITs such as FIB-4, TE, and ELF, new NITs are emerging to help stratify fibrosis risk and stage • There are genetic components that indicate risk for progression in patients with MASLD/MASH • GLP-1 RAs continue to be a treatment option for patients with cardiometabolic comorbidities and have shown some efficacy in treating MASH • Bariatric surgery can be considered for patients with MASH and have shown positive liver-related outcomes