Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis with Fibrosis

Inclusion Criteria:

• Males or females, between 18 and 75 years of age, both inclusive at screening.

• BMI ≤45 kg/m²

• Histological confirmation of NASH with liver fibrosis by central pathologist on adiagnostic liver biopsy with a NAS ≥4 with at least one-point score in each of thethree components of the NAFLD activity score [NAS] (steatosis scored 0-3, ballooningdegeneration scored 0-2, and lobular inflammation scored 0-3) and NASH by patternrecognition Note: The biopsy must not have been performed more than 24 weeks beforerandomization.

• The subjects must have a stable body weight (no more than 5% change) between thetime of biopsy and randomization.

• Fibrosis stage 2 and 3, according to the NASH CRN fibrosis staging, reported bycentral pathologist.

• If the subjects have type 2 diabetes mellitus, then it must be moderately controlledwith HbA1c ≤ 9.5% and on a stable dose of permitted anti-diabetic medication for atleast 90 days before screening until randomization.

• If the subjects are taking vitamin E > 400 IU/day, then it must be on a stable dosefor at least 24 weeks prior to screening or, if a historical biopsy is used, atleast 24 weeks prior to baseline liver biopsy until randomization.

• Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

• Consumption of >2 units of alcohol per day (>14 units per week) if male and >1 unitsof alcohol per day (>7 units per week) if female for at least 12 consecutive weekswithin 5 years before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wineor 1 ounce of spirits/hard liquor)

• History or presence of other concomitant liver diseases at screening:

1. Chronic hepatitis B (HBV) or hepatitis C virus (HCV) infection (However, If thesubject has been treated for the HCV infection and has been cured at least 5years from screening, such subjects can be enrolled in the study)

2. Primary biliary cholangitis (PBC)

3. Primary sclerosing cholangitis (PSC)

4. Definite autoimmune liver disease or overlap syndrome

5. Alcoholic liver disease

6. Hemochromatosis

7. Wilsons disease

8. Alpha-1 antitrypsin deficiency

• Subject with known cirrhosis, either based on histology, clinical criteria or anynon-invasive diagnostic modality, within 24 weeks prior to the randomization.

• Evidence of portal hypertension (low platelet count, esophageal varices, ascites,history of hepatic encephalopathy, splenomegaly) at screening.

• Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium glucosecotransporter- 2 (SGLT-2) inhibitors, and dipeptidyl peptidase 4 inhibitors (gliptins) unless stable for 120 days prior to screening or, if a historical biopsyis used, from 120 days prior to baseline liver biopsy until randomization.

• Use of concurrent medications prior to screening including:

1. Anti-NASH therapy(s) including S-adenosyl methionine (SAMe), ursodeoxycholicacid (UDCA), and obeticholic acid in the period from 90 days prior to screeningor, if a historical biopsy is used, from 90 days prior to baseline liver biopsyuntil randomization. For resmetirom; 120 days prior to screening or if ahistorical biopsy is used, from 120 days prior to baseline liver biopsy untilrandomization.

2. Antidiabetic mediation which may impact NASH histology includingthiazolidinediones (pioglitazone, rosiglitazone) in the period from 90 daysprior to screening or, if a historical biopsy is used, from 90 days prior tobaseline liver biopsy until randomization.

3. Immune modulatory agents including anti-TNF-α therapies (infliximab,adalimumab, etanercept) or anti-integrin therapy (namixilab) in the period from 28 days prior to screening or if a historical biopsy is used from 28 days priorto baseline liver biopsy until randomization.

4. Any treatment or anticipated initiation (intended use for more than 14consecutive days) of medications known to have an effect on steatosis (e.g.treatment with corticosteroids [topical and inhaled are allowed]),methotrexate, tamoxifen, valproic acid, amiodarone or tetracycline, estrogensin doses higher than used in oral contraceptives, vitamin A, L-asparaginase,valproate, chloroquine, or antiretroviral drugs in the period from 28 daysprior to screening or, if a historical biopsy is used, from 28 days prior tobaseline liver biopsy until randomization.

5. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin,bupropion, or naltrexone alone, or in combination or any other medication, thatcould promote weight loss, in the opinion of the investigator, in the periodfrom 28 days prior to screening or if a historical biopsy is used from 28 daysprior to baseline liver biopsy until randomization.

• Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin,fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, Fenofibrate) in the 90 days preceding screening until randomization.

• Use of drugs that are known CYP2C8 inhibitors/substrate in the 28 days precedingscreening until randomization.

• History of liver transplant

• Any weight reduction surgery in the 2 years prior to screening or planned during thestudy (weight reduction surgery is disallowed during the study), and malabsorptiveweight loss surgery (Rouxen-Y or distal gastric bypass) at any time prior toscreening.

Note: Lap banding, if the band has been removed >6 months before baseline liver biopsy, or intragastric balloon, if the balloon has been removed > 6 months before baseline liver biopsy, is allowed.

• Type 1 diabetes mellitus

• History of stomach or intestinal surgery or resection within the six months prior toscreening that would potentially alter absorption and/or excretion of orallyadministered drugs as judged by the investigator.

• Unstable cardiovascular disease, including:

1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease) inthe 90 days before screening and throughout the screening period; acutecoronary syndrome in the 24 weeks before screening and throughout the screeningperiod;

2. acute myocardial infarction in the 90 days before screening and throughout thescreening period; or heart failure of New York Heart Association class (III -IV), worsening congestive heart failure, or coronary artery intervention, inthe 24 weeks before screening and throughout the screening period.

3. history of unstable cardiac dysrhythmias

4. uncontrolled hypertension at screening

5. stroke or transient ischemic attack in the 24 weeks before screening

• History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5times ULN at screening.

• For subjects with elevated baseline ALT, AST, or ALP; ALT, AST, or ALP exceeding bymore than 50% at Visit 2 reading compared to Visit 1 Note: If the ALT, AST or ALPvalues at Visit 2 exceed by more than 50% from Visit 1, then a third value will bemeasured to assess for the trend. If the third value shows continued increase ≥ 10%,then subject is considered ineligible for randomization.

• Any of the following laboratory values at screening:

1. Hemoglobin <9 g/dL

2. WBC count <2.5 × 103/µL

3. Neutrophil count <1.5 × 103/µL

4. Platelets <140 × 103/µL [if low platelet count is due to reasons other thanliver disease as assessed by a hematologist, participants may be eligible ifthe platelet count is > 75 x 103/µL] as per investigator's discretion]

5. INR ≥ 1.3 (in the absence of anticoagulants)

6. Total bilirubin > ULN except in Gilbert's syndrome. In subjects with knownGilbert's syndrome, direct bilirubin > 2 x ULN

7. Albumin <3.5 g/dL

8. eGFR <60 mL/min/1.73 m2

9. ALP ≥ 2x ULN

10. ALT or AST ≥ 250 U/L

• Participation in any other therapeutic clinical study and on active treatment in thepast 90 days of the screening.

• History of benign or malignant bladder tumors, and/or hematuria or has currenthematuria except due to a urinary tract infection.

• History of malignancy in the past 5 years and/or active neoplasm with the exceptionof resolved superficial nonmelanoma skin cancer.

• Known allergy, sensitivity or intolerance to the study drug, comparator orformulation ingredients.

• Pregnancy-related exclusions, including:

1. Pregnant/lactating female (including positive pregnancy test at screening)

2. Pregnancy should be avoided by male and female participants either by trueabstinence or the use of an acceptable effective contraceptive measures for theduration of the study and for at least 1 month after the end of the studytreatment

• History or other evidence of severe illness or any other conditions that would makethe subject, in the opinion of the investigator, unsuitable for the study (such aspoorly controlled psychiatric disease, HIV, coronary artery disease or activegastrointestinal conditions that might interfere with drug absorption)

• Receiving an elemental diet or parenteral nutrition.

• Chronic pancreatitis or pancreatic insufficiency.