Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis

A Phase 2b, Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy and Safety of Saroglitazar Magnesium in Subjects with Nonalcoholic Steatohepatitis and 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 a diagnostic liver biopsy with a NAS ≥4 with at least one-point score in each of the three components of the NAFLD activity score [NAS] (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3) and NASH by pattern recognition Note: The biopsy must not have been performed more than 24 weeks before randomization.
• The subjects must have a stable body weight (no more than 5% change) between the time of biopsy and randomization.
• Fibrosis stage 2 and 3, according to the NASH CRN fibrosis staging, reported by central pathologist.
• If the subjects have type 2 diabetes mellitus, then it must be moderately controlled with HbA1c ≤ 9.5% and on a stable dose of permitted anti-diabetic medication for at least 90 days before screening until randomization.
• If the subjects are taking vitamin E > 400 IU/day, then it must be on a stable dose for at least 24 weeks prior to screening or, if a historical biopsy is used, at least 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 units of alcohol per day (>7 units per week) if female for at least 12 consecutive weeks within 5 years before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 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 the subject has been treated for the HCV infection and has been cured at least 5 years 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 any non-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 glucose cotransporter- 2 (SGLT-2) inhibitors, and dipeptidyl peptidase 4 inhibitors (gliptins) unless stable for 120 days prior to screening or, if a historical biopsy is 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), ursodeoxycholic acid (UDCA), and obeticholic acid in the period from 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline liver biopsy until randomization. For resmetirom; 120 days prior to screening or if a historical biopsy is used, from 120 days prior to baseline liver biopsy until randomization.
  2. Antidiabetic mediation which may impact NASH histology including thiazolidinediones (pioglitazone, rosiglitazone) in the period from 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline 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 prior to baseline liver biopsy until randomization.
  4. Any treatment or anticipated initiation (intended use for more than 14 consecutive 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, estrogens in doses higher than used in oral contraceptives, vitamin A, L-asparaginase, valproate, chloroquine, or antiretroviral drugs in the period from 28 days prior to screening or, if a historical biopsy is used, from 28 days prior to baseline liver biopsy until randomization.
  5. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion, or naltrexone alone, or in combination or any other medication, that could promote weight loss, in the opinion of the investigator, in the period from 28 days prior to screening or if a historical biopsy is used from 28 days prior 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 preceding screening until randomization.

• History of liver transplant

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

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 to screening that would potentially alter absorption and/or excretion of orally administered drugs as judged by the investigator.

• Unstable cardiovascular disease, including:

  1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease) in the 90 days before screening and throughout the screening period; acute coronary syndrome in the 24 weeks before screening and throughout the screening period;
  2. acute myocardial infarction in the 90 days before screening and throughout the screening period; or heart failure of New York Heart Association class (III - IV), worsening congestive heart failure, or coronary artery intervention, in the 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 ≥ 5 times ULN at screening.

• For subjects with elevated baseline ALT, AST, or ALP; ALT, AST, or ALP exceeding by more than 50% at Visit 2 reading compared to Visit 1 Note: If the ALT, AST or ALP values at Visit 2 exceed by more than 50% from Visit 1, then a third value will be measured 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 than liver disease as assessed by a hematologist, participants may be eligible if the 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 known Gilbert'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 the past 90 days of the screening.

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

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

• Known allergy, sensitivity or intolerance to the study drug, comparator or formulation 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 true abstinence or the use of an acceptable effective contraceptive measures for the duration of the study and for at least 1 month after the end of the study treatment

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

• Receiving an elemental diet or parenteral nutrition.

• Chronic pancreatitis or pancreatic insufficiency.

Double-blind Masking