Assessment of the Safety of Foralumab, an Oral Anti-CD3 Antibody, in Patients With NASH and T2DM

Inclusion Criteria:

• Age ≥ 18 years
• Provision of written informed consent
• Diagnosis of T2DM
• HbA1c < 9.0 while on standard of care
• Historical histology-based confirmation of NASH within 12 months prior to screening OR

Diagnosis of NAFLD based on all the following:

• Presentation of at least one other parameter of the metabolic syndrome from the following list of three:

  (i) hypertension [≥130/85 mmHg or regularly taking an antihypertensive], (ii) dyslipidemia with high serum triglycerides [≥150 mg/dL or regularly taking medicines to lower high triglyceride levels] or low serum HDL [<50 mg/dL for women and <40 mg/dL for men], (iii) obesity (BMI > 30 kg/m2) or central obesity [waistline measurement ≥ 89 cm for women and ≥ 102 cm for men])

• ALT > 40 IU
• Fat fraction >10% in MRI performed during screening or up to 3 months prior to screening.
• Agree to the use of effective contraceptive measures, as defined in the protocol, if either male or female with child-bearing potential.

Exclusion criteria:

• Subject with cirrhosis per biopsy (fibrosis staging score >= 4) or Fibroscan® >14 kPa within 12 months of screening.
• Presence of vascular liver disease
• Any history or evidence of decompensated liver disease such as recurrent variceal bleeding, refractory ascites or hepatic encephalopathy
• Known history of chronic alcoholic liver disease, chronic hepatitis B or C infection, drug-induced liver injury (DILI), hemochromatosis, Wilson's disease, 1-antitrypsin deficiency, primary biliary cirrhosis or secondary sclerosing cholangitis, autoimmune hepatitis
• Known HIV antibody-positive
• History of liver transplantation
• BMI <25kg/m2
• Clinically significant alcohol use
• Score of ≥ 2 on the CAGE questionnaire, OR
• Any subject with current significant alcohol consumption or a history of significant alcohol consumption for a period of more than 3 consecutive months any time within 1 year prior to screening, as determined by medical history (medical chart review and/or interview). Significant alcohol consumption is defined as: females: >20 g/day; males: >30 g/day, with a standard drink in the US averaging 14 g alcohol.
• Type 1 diabetes
• Bariatric surgery within the last 5 years
• Weight loss or gain of ≥5 kg in the past 6 months or >10% change in bodyweight in the past 12 months
• Inadequate vascular access on physical examination
• Lactating/breastfeeding/pregnant at screening
• On an elemental diet or parenteral nutrition
• Concurrent conditions
• Inflammatory bowel disease
• Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24 weeks of screening
• Ongoing infectious disease, excluding recurrent urinary tract infection treated with long-term antibiotic prophylaxis
• Any type of immune-mediated and/or malignant disease
• Any other concurrent condition which, in the opinion of the investigator, could impact adversely on the participating subject or on the interpretation of the study data
• Concurrent medications including:
• Amiodarone taken within 30 days of Day 1 (MBT contraindication)
• Beta-blockers: must be on a stable dose for at least 30 days prior to Day 1 (MBT contraindication)
• Statins: must be on a stable dose for at least 30 days prior to Day 1 (MBT contraindication)

• The following medications taken every day for more than 1 week over the last three months: S-adenosyl methionine (SAM-e), betaine, milk thistle and probiotic supplements (other than yoghurt) with the exception of vitamin E or gemfibrozil, which are allowed

  ** If >= 400 IU vitamin E on a regular basis or gemfibrozil, at any dose, are used, the dose must be stable for more than 3 months;

• immunomodulatory agents including In the last 4 weeks

  • oral or parenteral antibiotics
  • daily treatment with non-steroidal anti-inflammatory drugs (e.g., aspirin (>100 mg/day), ibuprofen, naproxen, imeloxicam, celecoxib)

In the last 3 months

• systemic steroids
• daily treatment with non-steroidal anti-inflammatory drugs (e.g., aspirin (>100mg/day), ibuprofen, naproxen, meloxicam, celecoxib) over 4 or more weeks in the last 3 months
• variable dose of antilipidemic agents (HMG Co-A reductase inhibitors - "statins"). Subjects on stable dose of statins are eligible if missed no more than one week of dosing over the last 3 months

In the last 12 months

o azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNF alpha therapies (infliximab, adalimumab, etanercept) or anti-integrin therapies

• Any of the following laboratory abnormalities:
• Neutrophil count ≤1.0 x 109/L
• Platelets <100 x 109/L
• Hemoglobin <10g/dL
• Albumin <3.5g
• International Normalized Ratio (INR) >1.5
• Total bilirubin >1.5 x upper limit of reference range (unless Gilbert's syndrome or extrahepatic source as denoted by increased indirect bilirubin fraction)
• Either creatinine clearance ≤60mL/minute, calculated by Cockroft Gault, or creatinine >1.5x upper limit of reference range
• Regular use of marijuana or marijuana-related products, or use of cocaine, or street drugs, as determined by medical history (medical chart review and/or interview).
• Subjects with symptoms of significant mental illness, inability to cooperate or communicate with the investigator, who are unlikely to comply with the study requirements, or who are unable to provide informed consent.
• Hypersensitivity to methacetin and/or its metabolites (i.e., paracetamol, acetaminophen)