A Randomized, Double-blind Study to Assess the Safety and Efficacy of EDP-305 in Subjects With Liver-biopsy Proven NASH

A Phase 2b Randomized, Double-Blind, Placebo-controlled, Multicenter Study Evaluating Safety and Efficacy of EDP-305 in Subjects With Liver Biopsy Proven Non-alcoholic Steatohepatitis (NASH) (ARGON-2)

A randomized, double-blind study to assess the safety and efficacy of EDP-305 in subjects with liver-biopsy proven Non-Alcoholic Steatohepatitis (NASH)

The aim of this Phase 2b study aimed to evaluate safety and efficacy of the investigational novel FXR agonist, EDP-305, in a population of patients with liver biopsy proven NASH.

This Phase 2b study aimed to evaluate the safety and efficacy of two doses of EDP-305 compared to placebo for the treatment of NASH in subjects with liver biopsy proven NASH. As suggested in the FDA guidance, this late stage Phase 2 study explored the effect of EDP-305/placebo treatment on histological endpoints. The patient population selected for inclusion in the study was designed to represent the target population for treatment. Specifically, in patients with liver disease, there is a significant overlap of NASH and various metabolic conditions including obesity and T2DM. In order to be reflective of the NASH population, these patients were not excluded from participation in this study.

Inclusion Criteria:

• Informed consent documentation signed and dated by the participant.
• Male and female participants, of all ethnic origins, between the ages of 18 and 75 years, inclusive.
• Participants of all ethnic origins had to have a Body Mass Index (BMI) > 25 kg/m2 and ≤ 45 except Asian participants who qualified for the study with BMI > 23 kg/m2.
• Histological evidence of definite NASH based on NASH Clinical Research Network (CRN) criteria obtained from assessment of a liver biopsy by the central histopathologist. The biopsy may be obtained either 1) during the Screening window or 2) within 26 weeks prior to the Screening visit.
• NAFLD Activity Score (NAS) of 4 or greater with a score of at least 1 in each component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2).
• Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System.
• Participants had to have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab) as seronegative. [Note: participants previously infected by chronic hepatitis C and treated with direct acting antivirals (DAAs) with sustained virologic response (SVR) for at least 3 years were allowed.]
• A woman of childbearing potential who was sexually active with a male had to agree to use two effective methods of contraception from the date of Screening until 30 days after the last dose of study drug.
• A male participant who had not had a vasectomy and was sexually active with a woman of childbearing potential had to agree to use effective contraception from the date of Screening to 90 days after the last dose of study drug.
• Participant had to be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol.

Exclusion Criteria:

• Laboratory Screening results as indicated below:

  • Total white blood cells (WBC) <3000 cells/mm3
  • Absolute neutrophil count (ANC) <1500 cells/mm3
  • Platelet count <140,000/mm3
  • International Normalized Ratio, INR >1.2 (unless due to use of anticoagulants)
  • Estimated glomerular filtration rate (eGFR) < 60 mL/min according to the Modification of Diet in Renal Disease (MDRD) equation
  • AST ≥5× ULN
  • ALT ≥5× ULN
  • ALP ≥2× ULN
  • Total bilirubin > 1.5 times ULN during Screening. [Note: Patients with Gilbert's syndrome were allowed following review by the Medical Monitor if they had a known history of Gilbert's syndrome with a normal direct bilirubin value and normal reticulocyte count.]

• Pregnant or nursing females.

• MELD: Model for End-stage Liver Disease score >12.

• Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC).

• History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute biliary obstruction) unless the participant had a cholecytectomy (more than 3 months prior to screening).

• History of liver transplant, or current placement on a liver transplant list.

• Hepatorenal syndrome (type I or II).

• Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks of Screening and/or histological presence of liver cirrhosis.

• Prior or planned ileal resection, or prior or planned bariatric surgery. [Note: Participants who had undergone gastric surgeries that did not affect drug absorption (e.g., gastric band or gastric sleeve procedures) were allowed if they were stable for at least 1 year prior to Screening. Gastrectomy or Roux-en-Y bypass was allowed if stable for at least 3 years prior to Screening.]

• Participants with clinically or otherwise documented cardiovascular or cerebrovascular disease including clinically significant anomalies of rhythm or pattern of ECG, that in the judgement of the Principal Investigator (PI) could affect the safety of the participant or their ability to comply with the study requirements.

• HbA1c ≥ 9.5% within 60 days prior to Day 1.

• Use of a new antidiabetic regimen in the months prior to Screening including metformin, glucagon-like peptide (GLP) 1 agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferator-activated receptor (PPAR)γ agonists (e.g., pioglitazone or rosiglitazone). For pre-existing antidiabetic treatment, participants were to be on a stable dose of antidiabetic drugs: (1) for at least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to Screening with the intention to keep the regimen stable during the study.

• Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to Screening.

• Use of a new fibrate regimen from 12 weeks prior to Screening.

• Participants with contraindications to MRI imaging, or not being able to have the MRI performed.

• Participant had received any investigational agent (including investigational vaccine) or biological product within 30 days or 5 times the half-life (whichever was longer) prior to the planned first dose of study drug.

• Use of an experimental or approved treatment for NASH within 26 weeks of Screening.

• Prior use of OCA within 26 weeks of Screening and/or concurrent treatment with OCA (or any other FXR agonists).

• Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in duration within 1 year prior to Screening with the intention to continue during the study (chronic use of inhaled, topical, ophthalmological, nasal corticosteroids was allowed)

• Use of any prohibited concomitant medications, including systemic CYP3A4 inhibitors and inducers, within 14 days prior to the first dose of study drug and for the duration of the study.

• Clinically significant history of drug sensitivity or drug allergy, as determined by the PI.

• Current or history of significant alcohol consumption defined as: >14 standard drinks per week and/or ≥4 standard drinks per occasion for males and >7 standard drinks per week and/or ≥3 standard drinks per occasion for females.

• History of substance (including alcohol) abuse and in the judgement of the PI, the participant was not suitable for participation in the study.

• Any other condition(s) that would compromise the safety of the participant or compromise the quality of the clinical study, as judged by the PI.

• Use of medication for weight loss or appetite reduction (e.g., orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin, non-prescription supplements) at Screening.

• History of malignancy of any organ system (other than localized and considered cured cutaneous basal or squamous cell carcinoma, or in situ cervical cancer), treated or untreated, within 5 years of Screening.