Saroglitazar Magnesium in the Treatment of Non-Alcoholic Steatohepatitis

Patients clinically suspected of NASH will be invited for a screening programme for inclusion
in the study. Patients will be screened according to the inclusion and exclusion criteria.
Clinical evaluation will be conducted for baseline characteristics and anthropometry
measurements such as body weight and height.

After clinical evaluations, all baseline safety and efficacy parameters will be recorded as
per Visit Schedule. All laboratory collections will be performed following overnight fasting
(at least 8 hrs).

Following confirmation of all clinical and laboratory inclusion and exclusion criteria,
patients will continue into the screening period. During the screening period liver biopsy
will be performed. However, if a biopsy was performed within 6 months the slides and biopsy
material, or block, must be made available for baseline documentation. Such Patients, whose
historical biopsy report is available, should not use medication suspected of having an
effect on NASH from the 3 months prior to the screening.

Liver biopsy will be performed to confirm the diagnosis of NASH and record a baseline NAFLD
Activity Score. The histological evidence of NASH is defined as NAS ≥ 4 with a minimum score
of 1 for all of its three components [steatosis, hepatocyte ballooning and lobular
inflammation].

Following confirmation of inclusion/exclusion criteria and upon histological confirmation of
NASH by liver biopsy, patients will be enrolled into the study.

Eligible patients will be randomly assigned to receive Saroglitazar Magnesium 2 mg or 4 mg or
placebo in a 2:2:1 ratio for 24 weeks.

Upon completion of 24 weeks of treatment, liver biopsy will be performed and the NAFLD
Activity Score recorded.

Inclusion Criteria:

1. Patients able to provide written informed consent for participation in this trial.

2. Males or females, 18 to 75 years of age, both inclusive.

3. Female must be either of non-child bearing potential (surgically sterilized at least 6
months prior to screening or postmenopausal) or using one or more methods of
contraception.

4. Histologic confirmation of NASH without cirrhosis (fibrosis stage 0, 1, 2, or 3) from
liver biopsy performed either during the screening period or no more than 6 months
prior to the first visit, with a NAS of ≥4 and a score of at least 1 in each
(steatosis scored 0-3, ballooning scored 0-2, and lobular inflammation scored 0-3). If
biopsy was performed within 6 months of screening, the slides, biopsy material or
block should be available for baseline documentation. Such patients, whose historical
biopsy report is available, should not use medications suspected of having an effect
on NASH for at least 3 months prior to the screening.

5. BMI ≥25 kg/m2.

6. For hypertensive patients, blood pressure must be controlled by a stable dose of
antihypertensive medications for at least 3 months prior to screening (and the stable
dose can be maintained throughout the study)

7. Patients with type 2 diabetes mellitus may be included if they fulfil the following
criteria;

1. Stable therapeutic regimen as defined by no changes in oral agents or dose for at
least 3 months before screening and the stable dose can be maintained throughout
the study.

2. HbA1c ≤ 9.5%

8. Patients agree to comply with the study procedure.

Exclusion Criteria:

1. Pregnant and lactating female.

2. Positive pregnancy test.

3. Patients with history of myopathies or evidence of active muscle diseases.

4. Patients with history of alcohol consumption of >30 gm/day for men, >20 gm/day for
women for consecutive previous 2 years and/or drug abuse.

5. Known allergy, sensitivity or intolerance to the study drug or formulation
ingredients.

6. Participation in an interventional clinical study and/or receipt of any
investigational medication within 3 months prior to screening.

7. History of malignancy in the past 5 years and/or active neoplasm with the exception of
superficial, non-melanoma, skin cancer.

8. Any of the following laboratory values at screening:

1. Direct bilirubin >1.5 mg/dL,

2. Serum albumin <2.5 g/dL.

3. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2.

4. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >200
IU/L.

5. Patient with international normalized ratio (INR) >1.5.

6. Creatinine kinase ≥ 1.5 ULN.

7. Lipase ≥ULN.

8. Amylase ≥ ULN.

9. Unstable cardiovascular disease, including:

1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease
within the 3 months preceding screening), acute coronary syndrome within the 6
months preceding Screening, acute myocardial infarction within the 3 months
preceding screening or heart failure of New York Heart Association class (III -
IV) or worsening congestive heart failure, or coronary artery intervention,
within the 6 months preceding screening

2. history of (within 3 months preceding Screening) or current unstable cardiac
dysrhythmias

3. uncontrolled hypertension (systolic blood pressure [BP] > 155 mmHg and/or
diastolic BP > 95 mmHg)

4. Stroke or transient ischemic attack within the 6 months preceding screening.

10. Previous history of bladder disease and/or hematuria.

11. Previous liver biopsy that demonstrated presence of cirrhosis or radiologic imaging
consistent with cirrhosis or portal hypertension.

12. Type 1 diabetes mellitus.

13. Use of drugs that are known CYP2C8 inhibitors/substrate.

14. Use of drugs associated with a clinical or histological picture consistent with fatty
liver disease or NASH for more than 12 consecutive weeks in the 1 year prior to start
of the study; (these include amiodarone, tamoxifen, methotrexate, glucocorticoids,
anabolic steroids, tetracyclines, estrogens, valproate/valproic acid, chloroquine,
anti-HIV drugs).

15. History of thyroid disease (hypothyroid patients who are euthyroid on thyroid hormone
replacement can be included).

16. History of, or current, cardiac dysrhythmias.

17. History of bariatric surgery, or undergoing evaluation for bariatric surgery.

18. Patients with a >10% weight loss in the 3 months prior to screening.

19. History or other evidence of severe illness or any other conditions that would make
the patient, in the opinion of the Investigator, unsuitable for the study (such as
poorly controlled psychiatric disease, coronary artery disease, HIV or active
gastrointestinal conditions that might interfere with drug absorption).

20. Patients on any treatment with other drugs used for treatment of NASH [pentoxyphyllin,
ursodeoxycholic acid, antioxidants such as vitamin E (>800 IU/day), glutathione,
orlistat, betaine, incretin mimetics or non-prescribed complementary alternative
medications (including dietary supplements, megadose vitamins, herbal preparations and
special teas)] or any medicine in clinical trials for NASH. (However, patients who are
taking stable dose of vitamin E for at least 3 months prior to screening will be
enrolled in the study).

21. History of other causes of chronic liver disease [autoimmune, primary biliary
cirrhosis, hepatitis B virus (HBV) and hepatitis C virus (HCV), Wilson disease,
alpha-1-antitrypsin deficiency, hemochromatosis etc.