Business decision

A phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and tolerability of denifanstat 50 mg compared to placebo in patients with metabolic dysfunction-associated steatotic liver disease (MALSD)/metabolic dysfunction-associated steatohepatitis (MASH) after 52 weeks of treatment.

Up to 2000 patients will be randomized to receive either denifanstat 50 mg or placebo.

Inclusion Criteria:

1. Willing and able to participate in the study and provide written informed consent.

2. Adults between 18 and 75 years of age.

3. Body mass index (BMI) ≥23 kg/m2 for Asian patients and ≥25 kg/m2 for patients of other races.

4. Presence of metabolic risk factor(s), as follows:

1. T2DM

   OR

2. At least 2 out of 4 of the following:

   • BMI ≥30 kg/m2,
   • Hypertension, or on active antihypertensive treatment
   • Elevated fasting serum TGs or on active treatment for hypertriglyceridemia
   • Reduced fasting serum HDL-c, or on active treatment for dyslipidemia.

5. For patients with T2DM:

1. HbA1c ≤9.5%
2. If treatment naive: patients must have been diagnosed for at least 12 weeks prior to screening

6. Suspected or confirmed diagnosis of MASH or MASLD or non-invasively diagnosed MASH or MASLD

7. Stable ALT and AST levels

Exclusion Criteria:

1. Previous intake of an approved MASH medication

2. Exclusionary laboratory values:

1. ALT and/or AST >5 × ULN.
2. ALP ≥2 × ULN.
3. Total serum bilirubin concentration >1.3 mg/dL.
4. Serum albumin concentration <3.5 g/dL.
5. International normalized ratio (INR) >1.3, except for patients receiving anticoagulant treatment.
6. Platelet count <140,000/μL.
7. Fasting TG level ≥500 mg/dL.
8. eGFR <45 mL/min/1.73 m2.

3. History of excessive alcohol intake for a period of more than 3 consecutive months within 1 year prior to screening.

4. Presence of cirrhosis on liver histology and/or cross-sectional imaging evidence consistent with cirrhosis and/or portal hypertension.

5. Current or historical clinically evident hepatic decompensation.

6. Evidence of another form of active liver disease.

7. Positive serologic evidence of current infectious liver disease.

8. MELD score ≥12.

9. Planned or history of liver transplantation.

10. Prior or planned bariatric surgery.

11. Gain or loss of >5% of body weight in the 3 months or >10% of body weight in the 6 months prior to screening, qualifying liver biopsy, and the baseline visit (V1).

12. Any of the following conditions or procedures within 6 months prior to the baseline visit (V1):

1. Myocardial infarction
2. Cardiac revascularization surgery
3. Unstable angina
4. Transient ischemic attack, stroke, or cerebrovascular disease

13. Unstable or undiagnosed arrhythmias.

14. Uncontrolled high BP.

15. Malignancy with a complete remission date within 5 years prior to the baseline visit (V1).

16. Any current or history of hepatocellular carcinoma.

17. Diabetes other than T2DM

18. Uncontrolled hypothyroidism.

19. Any other known serious disease or other disease which in the Investigator's opinion would exclude the patient from participating in the study.

20. Use of a nonpermitted concomitant medication within 30 days or 5 half-lives prior to screening.