Ascend-Nash: A Phase 2b, Randomized, Multi-Center, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy And Safety Of Crv431 In Adult Subjects With Nonalcoholic Steatohepatitis And Advanced Liver Fibrosis

• Inclusion Criteria:
• Male or female between 18 and 75 years of age (inclusive).
• Capable of giving written informed consent and able to effectively communicate with the investigator and study personnel. A signed informed consent form (ICF) must be on file prior to initiating the Screening procedures.
• Willing and able to complete all study requirements, restrictions, visits and procedures.
• Histologic evidence of NASH based on central readings of the screening biopsy obtained no more than 6 months before Screening defined by presence of all 3 key histological features, Nonalcoholic Fatty Liver Disease Activity Score (NAS) ≥ 4 with at least 1 point each in lobular inflammation and hepatocyte ballooning.
• Historical biopsy may be substituted for Screening biopsy to determine eligibility if the following are met:
• Historical biopsy was obtained no more than 180 ± 5 days prior to the first day of screening.
• Hepatic tissue or slides are available for central histologic evaluation.
• No new therapeutic intervention for NASH was made 90 days prior to screening (e.g., obeticholic acid, vitamin E ≥ 400 IU/day, pioglitazone, incretins [e.g., liraglutide, semaglutide], sodium-glucose cotransporter-2 [SGLT2] inhibitors).
• Subjects must have been metabolically stable since the biopsy (no significant weight loss ≥ 7% of body weight, no major deterioration of glycemic control, and no introduction of new or investigational drugs for the treatment of Type 2 Diabetes).
• Histologic liver fibrosis stage 2 or 3 as defined by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) scoring of liver fibrosis based on central reading of the Screening biopsy (refer to criteria 4a regarding use of a historical biopsy as a substitute for the Screening biopsy).
• Blood pressure up to 160/100 mmHg; potential subjects who meet other eligibility requirements, but who have out of range blood pressure measurements deemed to be not clinically significant by the investigator, may still be considered for study inclusion.
• Females of reproductive potential, defined as women who have not been postmenopausal for at least 12 consecutive months (i.e., who have had menses within the preceding 12 months), or women who have not undergone surgical sterilization, specifically, hysterectomy, bilateralsalpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, must have a negative pregnancy test at Screening and prior to dosing at Day 1.
• All participants must agree not to participate in a conception process (i.e., active attempt to become pregnant or to impregnate, sperm or egg donation, in vitro fertilization). If participating in sexual activity that could lead to pregnancy, the participant must agree to use 2 reliable methods of contraception simultaneously while receiving study treatment and for 3 months after subject has stopped taking study drug. A combination of TWO of the following methods MUST be used appropriately:
• Condoms (male or female) with or without a spermicidal agent.
• Diaphragm or cervical cap with spermicide.
• Intrauterine device (IUD).
• Hormonal-based contraception.

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Note: Participants who are not of reproductive potential (women who have been postmenopausal for at least 12 consecutive months or have undergone hysterectomy, bilateral salpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, or men who have documented azoospermia) are eligible without requiring the use of contraceptives. Acceptable documentation of sterilization, menopause or male partner’s azoospermia must be provided; serum follicle stimulating hormone (FSH) measurement can be used to document menopausal status.

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Exclusion Criteria:**

• Pregnant or breastfeeding or planning to become pregnant during the study period.
• Known allergy to Rencofilstat, cyclosporine, or any of their inactive ingredients.
• Positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus antibodies (HIVAb). If HCVAb test is positive, then an HCVRNA test will be performed. If this test is negative, the subject is allowed to participate in the study, as long as the subject meets all other inclusion criteria and has never been treated for HCV or was treated >2 years ago and achieved a sustained virologic response at that time.
• Subjects with suspected and symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified prior to first dose.
• History of or any current medical condition which could compromise the safety of the participant in the study, as determined by the investigator.
• Clinically significant gastrointestinal, cardiovascular, neurologic, psychiatric, renal, hepatic, respiratory, inflammatory, or infectious disease, as determined by the investigator.
• Subjects with a history of clinically significant acute cardiac events within 30 days prior to Screening such as stroke, transient ischemic attack, or coronary heart disease (angina pectoris requiring therapy, myocardial infarction, revascularization procedures with left ventricular ejection fraction [LVEF] <50% as determined by previous echocardiography or multiple gated acquisition [MUGA] scan).
• Subjects with uncontrolled or unstable cardiac arrhythmias:
• Severe conduction disturbance (e.g., second-degree or third-degree AV block).
• History of congenital long QT syndrome, congenital short QT syndrome, Torsades de Pointes, or Wolff Parkinson White syndrome.
• Safety laboratory abnormalities at Screening which are clinically significant as determined by the investigator.
• Subjects with transaminases >5 x upper limit of normal (ULN).
• Subjects with ALP >2 x ULN.
• Subjects with total serum bilirubin >1.5 x ULN.
• Subjects with a platelet count <100,000/mm3.
• Subjects with an INR ≥ 1.3 in the absence of anticoagulants.
• Subjects with albumin <3.5 g/dL.
• Model for End-Stage Liver Disease (MELD) score >12, unless due to an alternate etiology such as therapeutic anticoagulation.
• Current or previous (within the past 6 months) Child-Pugh (CP) score ≥ 7 for F2 or F3 subjects, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation.
• An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (calculated by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] method).
• Subjects with hemoglobin A1c (HbA1c) >9.5%.
• Use of systemic immunosuppression therapies within 6 months prior to the first dose of study drug apart from short-term treatment for asthma, inclusive of agents targeting arthritic conditions or chronic skin conditions.
• Current clinically significant diarrhea or gastric stasis that in the investigator’s opinion could influence drug absorption or bioavailability.
• Subjects with any history or presence of decompensated cirrhosis including ascites, hepatic encephalopathy or variceal bleeding.
• Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to:
• Suspicion of drug-induced liver disease.
• Alcoholic liver disease.
• Autoimmune hepatitis.
• Wilson’s disease.
• Primary biliary cholangitis, primary sclerosing cholangitis.
• Genetic hemochromatosis (Homozygosity for C282Y or C282Y/H63D compound heterozygote).
• Known or suspected hepatocellular carcinoma (HCC).
• History or planned liver transplant.
• Clinical evidence of portal hypertension such as esophageal varices, ascites, history of hepatic encephalopathy, or splenomegaly.
• History of hepatic decompensating events or subjects who develop manifestations of hepatic decompensation between screening and enrollment should not be randomized, inclusive of new or worsening jaundice and ascites, new esophageal varices, etc.
• Subjects with Type 2 diabetes who have recent (< 3 months) changes in medication class or dose of the following antidiabetic medications: Glucagon-like-peptide-1 (GLP-1) receptor agonist, dipeptidyl peptidase-4 (DPP-4) inhibitor, sodium/glucose cotransporter 2 (SGLT2) inhibitor, thiazolidinediones (TZD).
• Weight loss of more than 7% within 3 months prior to randomization.
• Current abuse of alcohol or illicit drugs, or history of alcohol or illicit drug abuse within the preceding 2 years, as determined by the investigator. History of excess alcohol intake as defined by ≥21 units of alcohol per week in males and ≥14 units of alcohol per week in females for 2 years prior to enrollment where a “unit” of alcohol is equivalent to 12-ounce beer, 4-ounce of wine, or 1-ounce shot of hard liquor.
• Judgement by the investigator that the subject should not participate in the study if the subject is unsuitable for the study or unlikely to comply with all study procedures and treatment.
• Received an investigational drug or investigational vaccine or used an investigational medical device within 60 days prior to first dose of study drug.
• Received any investigation products being evaluated for the treatment of liver fibrosis or NASH in the 6 months prior to the Screening liver biopsy.
• Subjects with a history of or planned organ transplantation. Corneal transplantation will be allowed.
• Inability to undergo MRE procedure due to unremovable metal or foreign object(s) or contraindication for any other reason including but not limited to pacemaker, shrapnel injury, extensive tattoos, severe claustrophobia, ear (cochlea) implant.
• (Vital signs, abnormal electrocardiogram (ECG) or laboratory parameters may be repeated once, if in the opinion of the investigator, the results are due to technical factors or based on PI judgement. Potential study subjects who met all inclusion and none of the exclusion criteria for this study but who, for personal or administrative reasons, were not included in a study cohort may be re-screened if more than 60 days have passed since their previous Screening. There are no restrictions on the number of rescreens permitted for these subjects.)