Dosing regimens of MAdCAM-1 antibodies for the treatment of nonalcoholic steatohepatitis

Abstract

The present disclosure provides, inter alia, MAdCAM-1 antibody treatment regimens for patients susceptible to or diagnosed with non-alcoholic steatohepatitis.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 384,723, filed November 22, 2022, U.S. Provisional Application No. 63 / 502,322, filed May 15, 2023, and U.S. Provisional Application No. 63 / 597,487, filed November 9, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Incorporation by reference of sequence listing The contents of the 56KB text file named "SHR-2026_Sequence Listing.xml", created on November 20, 2023, are incorporated herein by reference in their entirety.

[0003] Technical Field The present invention relates to dosing regimens of MAdCAM-1 antibodies for the treatment of nonalcoholic steatohepatitis (NASH). [Background technology]

[0004] Nonalcoholic steatohepatitis is a non-benign disorder characterized by significant health risks.Those diagnosed with NASH have significantly higher morbidity and mortality risks.Specifically, NASH is characterized by a high risk of cardiovascular and liver-related mortality.NASH can cause liver cirrhosis, which can then lead to fluid retention, muscle wasting, intestinal bleeding, and liver failure.Liver transplantation is the only treatment for advanced liver cirrhosis accompanied by liver failure, and NASH is currently the second most common reason for liver transplantation.

[0005] Therefore, there is a continuing need for therapeutic agents for the treatment of NASH. Summary of the Invention

[0006] The present invention relates to a dosing regimen for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis (NASH), comprising administering to the patient a therapeutic amount of a MAdCAM-1 antibody.

[0007] In one aspect, the invention provides a method for treating a patient susceptible to or diagnosed with NASH, comprising administering to the patient a therapeutic amount of about 20 mg to about 125 mg of a MAdCAM-1 antibody. In some embodiments, the method comprises administering a subsequent dose of the MAdCAM-1 antibody.

[0008] In some embodiments, either or both of the therapeutic dose and subsequent doses of the MAdCAM-1 antibody have a lower limit of 1 mg, 2 mg, 2.25 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg and an upper limit of 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg. mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, less than 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.

[0009] In some embodiments, the method includes administering to the patient a therapeutic amount of 22.5 mg or 75 mg of a MAdCAM-1 antibody. In some embodiments, the method includes administering to the patient a therapeutic amount of 75 mg of a MAdCAM-1 antibody.

[0010] In some embodiments, the MAdCAM-1 antibody comprises a light chain CDR1 of SEQ ID NO: 11, a light chain CDR2 of SEQ ID NO: 12, and a light chain CDR3 of SEQ ID NO: 13, and a heavy chain CDR1 of SEQ ID NO: 14, a heavy chain CDR2 of SEQ ID NO: 15, and a heavy chain CDR3 of SEQ ID NO: 16.

[0011] In some embodiments, the MAdCAM-1 antibody comprises a variable light chain of SEQ ID NO:3 and a variable heavy chain of SEQ ID NO:4.

[0012] In some embodiments, the MAdCAM-1 antibody comprises SEQ ID NO:1 for the light chain and SEQ ID NO:2 for the heavy chain.

[0013] In some embodiments, the subsequent doses are administered in amounts equal to or less than the therapeutic dose, and the subsequent doses are administered between about 1 week and about 12 weeks after the therapeutic dose. In some embodiments, the subsequent doses are administered every 4 weeks. In some embodiments, the subsequent doses are administered every 8 weeks.

[0014] In some embodiments, the MAdCAM-1 antibody is administered to the patient subcutaneously. In some embodiments, the MAdCAM-1 antibody is administered to the patient intravenously.

[0015] In some embodiments, the patient is not taking a TNF antagonist or TNF inhibitor.

[0016] In one embodiment, the MAdCAM-1 antibody is for use in the methods described herein.

[0017] In one embodiment, the pharmaceutical composition comprises a MAdCAM-1 antibody described herein.

[0018] In one aspect, the use of a MAdCAM-1 antibody is in the manufacture of a medicament for the treatment of non-alcoholic steatohepatitis.

[0019] In another aspect, the present invention provides a method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis (NASH), comprising administering to the patient a therapeutic amount of 22.5 mg or 75 mg of a MAdCAM-1 antibody comprising a light chain CDR1 of SEQ ID NO: 11, a light chain CDR2 of SEQ ID NO: 12, and a light chain CDR3 of SEQ ID NO: 13, and a heavy chain CDR1 of SEQ ID NO: 14, a heavy chain CDR2 of SEQ ID NO: 15, and a heavy chain CDR3 of SEQ ID NO: 16.

[0020] In another aspect, the invention provides the use of a MAdCAM-1 antibody for the manufacture of a medicament for the retreatment of nonalcoholic steatohepatitis (NASH).

[0021] In another aspect, the invention provides a MAdCAM-1 antibody for use in treating nonalcoholic steatohepatitis (NASH).

[0022] In another aspect, the present invention provides a method for assessing whether a patient has a beneficial response after subcutaneous administration of a 22.5 mg or 75 mg dose of a MAdCAM-1 antibody to patients with non-alcoholic steatohepatitis (NASH) at different stages of liver fibrosis, comprising: (a) measuring the levels of biomarkers in a biological sample from the patient, wherein the biomarkers are (i) neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3) and (ii) Enhanced Liver Fibrosis (ELF) score; and (b) comparing the levels with a control, wherein a change in the level of the biomarker compared to the control predicts a beneficial response in the patient.

[0023] In one aspect, a method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis comprises administering to the patient a therapeutic amount of 25 mg to 150 mg of a MAdCAM-1 antibody.

[0024] In some embodiments, the method comprises administering a subsequent dose of a MAdCAM-1 antibody.

[0025] In some embodiments, the methods include either or both of a therapeutic dose and subsequent doses of a MAdCAM-1 antibody, which have a lower limit of 1 mg, 2 mg, 2.25 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg and an upper limit of 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg. mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, less than 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.

[0026] In some embodiments, the methods comprise administering to the patient a therapeutic amount of 25 mg, 75 mg, or 150 mg of a MAdCAM-1 antibody.

[0027] In some embodiments, the methods comprise administering to the patient a therapeutic amount of 25 mg of a MAdCAM-1 antibody.

[0028] In some embodiments, the methods comprise administering to the patient a therapeutic dose of 75 mg of a MAdCAM-1 antibody.

[0029] In some embodiments, the methods comprise administering to the patient a therapeutic dose of 150 mg of a MAdCAM-1 antibody.

[0030] In some embodiments, the subsequent dose is administered in an amount that is the same as or less than the therapeutic dose, and the subsequent dose is administered between about 1 week and about 12 weeks after the therapeutic dose.

[0031] In some embodiments, the subsequent dose is administered between about 1 week and about 24 weeks after the therapeutic dose.

[0032] In some embodiments, the subsequent dose is administered between about 1 week and about 52 weeks after the therapeutic dose.

[0033] In some embodiments, the subsequent dose is administered between about 1 week and about 72 weeks after the therapeutic dose.

[0034] In some embodiments, the subsequent dose is administered between about 1 week and about 104 weeks after the therapeutic dose.

[0035] In one aspect, a method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis comprises administering to the patient a therapeutic amount of 25 mg, 75 mg, or 150 mg of a MAdCAM-1 antibody comprising a light chain CDR1 of SEQ ID NO: 11, a light chain CDR2 of SEQ ID NO: 12, and a light chain CDR3 of SEQ ID NO: 13, and a heavy chain CDR1 of SEQ ID NO: 14, a heavy chain CDR2 of SEQ ID NO: 15, and a heavy chain CDR3 of SEQ ID NO: 16.

[0036] In some embodiments, the methods comprise administering to the patient a therapeutic amount of 25 mg of a MAdCAM-1 antibody.

[0037] In some embodiments, the methods comprise administering to the patient a therapeutic dose of 75 mg of a MAdCAM-1 antibody.

[0038] In some embodiments, the methods comprise administering to the patient a therapeutic dose of 150 mg of a MAdCAM-1 antibody. [Brief explanation of the drawings]

[0039] [Figure 1]

[0023] Figure 1 shows a schematic diagram of the study design, showing all three study periods: screening, treatment, and safety follow-up. The various terms used in the study design schematic are detailed herein. [Figure 2] FIG. 1 shows MRI and Fibroscan imaging readouts from a subject with liver fibrosis (fibroinflammation) or steatosis (LSM = liver stiffness measurement; CAP = controlled attenuation parameter; cT1 = iron-corrected T1 mapping; PDFF = proton density fat fraction; LB = liver biopsy). DETAILED DESCRIPTION OF THE INVENTION

[0040] The term "screening" refers to screening of participants with NASH (Nonalcoholic Fatty Liver Disease Activity Score (NAS) ≥ 4) and F4 fibrosis (i.e., cirrhosis). The screening period will be extended up to 24 weeks for four F2 / F3 participants who have received at least three doses of MAdCAM-1 antibody and have been monitored for at least 12 weeks, until safety and tolerability information is available.

[0041] The term "liver biopsy" indicates that eligibility for liver biopsy at week -6 will be determined based on the results of the week -8 (SV1) assessment (Fibrosis-4 Index Score (FIB-4) ≥ 1.2, FibroScan-Aspartate Aminotransferase Score (FAST) ≥ 0.35, Pro-C3 ≥ 12.6 ng / mL, Enhanced Liver Fibrosis Score (ELF) ≥ 7.7, and liver chemistry eligibility criteria). For participants who meet other eligibility criteria at week -8 (SV1), if ALT or AST is > 4x ULN but < 5x ULN at week -8 (SV1), ALT / AST results at week -6 (SV2) will also be assessed prior to liver biopsy, and an abdominal MRI may be performed.

[0042] Pro-C3 and ELF scores are defined by the average of two measurements taken two weeks apart. Only participants with a biopsy-confirmed diagnosis of NASH (NAS score ≥ 4, with at least 1 point each for steatosis, ballooning, and lobular inflammation) and liver fibrosis stage 2, 3, or 4 will be enrolled in the study. Eligible previous liver biopsies will be accepted if formalin-fixed, paraffin-embedded (FFPE) liver blocks are available for further histological analysis and participants meet the inclusion criteria of Pro-C3 ≥ 12.6 ng / mL and ELF ≥ 7.7.

[0043] The term "liver tests" indicates that the liver tests included are alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma glutamyl transferase (GGT), and albumin.

[0044] The term "biomarker" indicates that the biomarkers included are neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3), enhanced liver fibrosis (ELF) score, soluble MAdCAM-1 (sMAdCAM-1), high-sensitivity C-reactive protein (hsCRP), IL-8, calprotectin (serum), circulating T cell signatures (e.g., Th17 / Th1 to Th2 ratio), CCR9, and CXCR3.

[0045] Abbreviations in the study design schematic are defined here: CAP stands for Controlled Attenuation Parameter, F stands for fibrosis stage, hsCRP stands for high-sensitivity C-reactive protein, IL stands for interleukin, LSM stands for liver stiffness measurement, Pro-C3 stands for neoepitope-specific N-terminal pro-peptide of type III collagen, Q4W stands for every 4 weeks, and sMAdCAM-1 stands for soluble mucosal addressin cell adhesion molecule 1.

[0046] definition In order that the present invention may be more readily understood, certain terms are first defined below. Further definitions of these and other terms are set forth throughout the specification.

[0047] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells (including mixtures thereof).

[0048] Antibody: As used herein, the term "antibody" or "Ab" or "Abs" or "mAbs" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen. "Specifically binds" or "immunoreacts with" means that the antibody reacts with one or more regions of the desired antigen. Antibodies include antibody fragments. Antibodies also include polyclonal, monoclonal, chimeric dAbs (domain antibodies), single chain, F ab , F ab’ , F (ab’)2 Fragments, scFvs, and F ab These include, but are not limited to, expression libraries. The antibody can be a complete antibody, or an immunoglobulin, or an antibody fragment.

[0049] Recognized immunoglobulin polypeptides include kappa and lambda light chains and alpha, gamma (IgG1, IgG2, IgG3, IgG4), delta, epsilon, and mu heavy chains, or equivalents in other species. A full-length immunoglobulin "light chain" (about 25 kDa or about 214 amino acids) contains a variable region of about 110 amino acids at the NH2-terminus and a kappa or lambda constant region at the COOH-terminus. A full-length immunoglobulin "heavy chain" (about 50 kDa or about 446 amino acids) similarly contains a variable region (about 116 amino acids) and one of the previously described heavy chain constant regions, e.g., the gamma heavy chain constant region (about 330 amino acids).

[0050] Antigen-binding site: As used herein, the term "antigen-binding site" or "binding portion" refers to the portion of an immunoglobulin molecule that participates in antigen binding. The antigen-binding site is formed by amino acid residues from the N-terminal variable ("V") regions of the heavy ("H") and light ("L") chains. Three highly divergent regions within the V regions of the heavy and light chains are called "hypervariable regions" and are sandwiched between more conserved adjacent regions known as "framework regions" or "FRs." Thus, the term "FR" refers to the amino acid sequences naturally found sandwiched between and adjacent to the hypervariable regions of immunoglobulins. In an antibody molecule, the three hypervariable regions of the light chain and the three hypervariable regions of the heavy chain are arranged relative to each other in three-dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are called "complementarity-determining regions" or "CDRs."

[0051] Approximately or About: As used herein, the term "approximately" or "about" as applied to one or more values ​​of interest refers to a value similar to the stated reference value. In certain embodiments, unless otherwise stated or otherwise clear from the context, the term "approximately" or "about" refers to a range of values ​​that is 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (above or below) from the stated reference value (except where such number would exceed 100% of possible values).

[0052] Biologically active: As used herein, the phrase "biologically active" refers to the characteristic of any agent that has activity in a biological system, particularly an organism. For example, an agent that, when administered to an organism, has a biological effect on that organism is considered biologically active. In certain embodiments, when a peptide is biologically active, the portion of the peptide that shares at least one biological activity of the peptide is typically referred to as a "biologically active" portion.

[0053] Epitope: As used herein, the term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or fragment. Epitopic determinants usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. For example, antibodies can be raised against N- or C-terminal peptides of a polypeptide.

[0054] Functional equivalent or derivative: As used herein, the term "functional equivalent" or "functional derivative," in the context of a functional derivative of an amino acid sequence, refers to a molecule that retains a biological activity (either function or structure) substantially similar to that of the original sequence. Functional derivatives or equivalents may be naturally occurring or synthetically prepared. Exemplary functional derivatives include amino acid sequences with one or more amino acid substitutions, deletions, or additions, provided that the biological activity of the protein is preserved. The substituted amino acid(s) desirably have similar chemical and physical properties to the substituted amino acid(s). Desirable similar physicochemical properties include similar charge, bulk, hydrophobicity, hydrophilicity, etc.

[0055] In vitro: As used herein, the term "in vitro" refers to events that take place in an artificial environment rather than within a multicellular organism, e.g., in a test tube or reaction vessel, in cell culture, etc.

[0056] In vivo: As used herein, the term "in vivo" refers to events that occur within a multicellular organism, such as humans and non-human animals. In the context of cell-derived systems, the term can be used to refer to events that occur within living cells (as opposed to, for example, in vitro systems).

[0057] Polypeptide: As used herein, the term "polypeptide" refers to a continuous chain of amino acids linked together via peptide bonds. The term is used to refer to an amino acid chain of any length, although those of skill in the art will understand that the term is not limited to long chains and may refer to a minimal chain comprising two amino acids linked via a peptide bond. Polypeptides may be processed and / or modified, as known to those of skill in the art.

[0058] Prevent: As used herein, the terms "prevent" or "prevention," when used in reference to the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition.

[0059] Protein: The term "protein," as used herein, refers to one or more polypeptides that function as a separate unit. When a single polypeptide is a separate functional unit and does not require permanent or temporary physical association with other polypeptides to form the separate functional unit, the terms "polypeptide" and "protein" may be used interchangeably. When a separate functional unit is composed of multiple polypeptides that are physically associated with each other, the term "protein" refers to the multiple polypeptides that are physically associated and function together as a separate unit.

[0060] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Humans include prenatal and postnatal forms. In many embodiments, a subject is a human. A subject may be a patient, which refers to a person who visits a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be suffering from or susceptible to a disease or disorder, but may or may not exhibit symptoms of such disease or disorder.

[0061] Substantially: As used herein, the term "substantially" refers to a qualitative state that exhibits all or nearly all extent or degree of a characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, go to and / or proceed to completion or reach or avoid an absolute result. Thus, the term "substantially" is used herein to express the potential lack of completeness inherent in many biological and chemical phenomena.

[0062] Substantial homology: The phrase "substantial homology" is used herein to refer to a comparison between amino acid or nucleic acid sequences. As will be understood by those skilled in the art, two sequences are generally considered "substantially homologous" if they contain homologous residues at corresponding positions. Homologous residues may be identical residues. Alternatively, homologous residues may be non-identical residues that have, as appropriate, similar structural and / or functional characteristics. For example, as is well known to those skilled in the art, certain amino acids are typically classified as "hydrophobic" or "hydrophilic" amino acids and / or as having "polar" or "non-polar" side chains. Substitution of one amino acid with another amino acid of the same type can often be considered a "homologous" substitution.

[0063] Suffering from: An individual who is "suffering from" a disease, disorder, and / or condition has been diagnosed with or exhibits one or more symptoms of that disease, disorder, and / or condition.

[0064] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount sufficient, when administered to a patient suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of a symptom(s) of such disease, disorder, and / or condition. Those skilled in the art will recognize that a therapeutically effective amount is typically administered by a dosing regimen comprising at least one unit dose. In the context of therapeutic (including prophylactic) applications, the amount of active agent administered to a patient will vary depending on the type and severity of the disease or condition, as well as on the patient's characteristics, such as overall health, age, sex, weight, and drug tolerance. It will also vary depending on the extent, severity, and type of disease or condition. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors.

[0065] Treating: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to patients who do not show signs of the disease and / or who show only early signs of the disease, with the intent of reducing the risk of developing pathology associated with the disease.

[0066] The recitation herein of numerical ranges by endpoints includes all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.9, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term "about."

[0067] Various aspects of the present invention are detailed in the following paragraphs. The use of a paragraph is not intended to limit the invention. Each paragraph may apply to any aspect of the present invention. In this application, the use of "or" means "and / or" unless otherwise stated.

[0068] Abbreviation In order to make the present invention easier to understand, certain abbreviations have been used and are first defined below in Table 1. Additional abbreviations for the following terms and other terms are described throughout the specification.

[0069] [Table 1-1]

[0070] [Table 1-2]

[0071] [Table 1-3]

[0072] [Table 1-4]

[0073] [Table 1-5]

[0074] Detailed Description Embodiments of the present disclosure are described below, but it should be clearly noted that the present disclosure is not limited to these embodiments, but rather is intended to include modifications and equivalents thereof that are obvious to those skilled in the art.

[0075] The present invention is directed to dosing regimens for administering mucosal addressin cell adhesion molecule-1 (MAdCAM-1; also known as addressin) antagonist antibodies to patients with nonalcoholic steatohepatitis (NASH). In one aspect, the invention features a method for treating nonalcoholic steatohepatitis (NASH), comprising administering to a patient in need thereof an effective amount of a MAdCAM-1 antibody.

[0076] Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the obesity epidemic. NAFLD is generally considered a group of liver diseases in which hepatic steatosis (or "fatty liver"), a buildup of triglycerides within hepatocytes, develops in the absence of secondary causes (e.g., medication, excessive alcohol consumption, or certain hereditary conditions).

[0077] Patients with NAFLD are at high risk for cardiovascular morbidity and mortality (Chalasani et al., "The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases", Hepatology, 67(1), 328-357 (2018). Nonalcoholic steatohepatitis (NASH) is an inflammatory subtype of NAFLD, characterized by steatosis and evidence of hepatocellular injury (ballooning) and inflammation, with or without fibrosis (Chalasani et al. 2018). Although often clinically asymptomatic, NASH with fibrosis can progress to cirrhosis, an end-stage liver disease, and some patients require liver transplantation. More than 20% of patients with NASH will develop cirrhosis during their lifetime (Matteoni et al., "Nonalcoholic fatty liver disease: a spectrum of clinical and pathological Severity”, Gastroenterology, 116(6), 1413-1419 (1999)), and patients with NASH are also at increased risk of developing hepatocellular carcinoma (Stine et al., “Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases”, Aliment Pharmacol Ther, 48(7), 696-703 (2018)).Between 2004 and 2016, the number of people on the liver transplant waiting list due to NASH expanded by 114% and 80% in men and women, respectively (Noureddin et al., “NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances”, Am J Gastroenterol, 113(11), 1649-1659 (2018)). NASH is now the leading indication for liver transplantation in women and is expected to overtake alcoholic liver disease as the leading indication for liver transplantation for all patients within the next few years (Noureddin et al. 2018). NASH has an annual mortality rate 1.7 times higher than that of NAFLD overall (25.56 vs. 15.44 cases per 1000 person-years), and liver-specific mortality is 15 times higher than that of NAFLD (11.77 vs. 0.77 cases per 1000 person-years) (Younossi et al., "Global epidemiology of nonalcoholic fatty liver disease - Meta-analytic assessment of prevalence, incidence, and outcomes", Hepatology, 64(1), 73-84(2016)).

[0078] Currently, the first-line treatment for NAFLD / NASH is lifestyle modification for weight loss through diet and exercise (Guirguis et al., "Emerging therapies for the treatment of nonalcoholic steatohepatitis: A systematic review", Pharmacotherapy, 41(3), 315-28(2021); Sheka et al., "Nonalcoholic steatohepatitis: A Review. Jama, 323(12), 1175-1183(2020)). Meta-analysis studies have shown that a weight loss of 7% or more is associated with an improvement in the nonalcoholic fatty liver disease activity score (NAS) (Musso et al., "Impact of current treatments on liver disease, glucose metabolism, and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomized Although dietary composition appears to influence hepatic fat deposition, no specific macronutrient diet has been shown to be beneficial for NASH. Therefore, calorie restriction is the most appropriate recommendation for these patients (Chalasani et al. 2018).

[0079] Vitamin E and pioglitazone have shown some benefit in clinical trials. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has demonstrated improvements in insulin sensitivity, aminotransferase levels, steatosis, inflammation, and ballooning in patients with NASH and prediabetes or type 2 diabetes mellitus (T2DM) (Belfort, “Metabolic and histologic improvement in non-alcoholic steatohepatitis (NASH) during pioglitazone (PIO) treatment is associated with a reduction in inflammatory markers,” Abstract No. 439-P, American Diabetes Association 66th Scientific Sessions, 9-13 June 2006, Washington, DC. American Diabetes Association).

[0080] For patients with NASH, pharmacotherapy options are currently limited to the off-label use of pioglitazone and vitamin E due to a lack of large randomized trials evaluating these treatments. However, to date, no pharmacotherapy has been approved for NASH by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0081] MAdCAM-1 MAdCAM-1 (also known as addressin) is a member of the immunoglobulin superfamily of cell adhesion receptors. The selectivity of lymphocyte homing to specialized lymphoid tissues and mucosal sites in the gastrointestinal tract is determined by endothelial expression of MAdCAM-1. MAdCAM-1 is specifically expressed on the cell surface of high endothelial venules in organized intestinal lymphoid tissues, such as Peyer's patches and mesenteric lymph nodes, but is also expressed in other lymphoid organs, such as the pancreas, gallbladder, and splenic venules and marginal sinuses of the white pulp of the spleen.

[0082] MAdCAM-1 plays a physiological role in intestinal immune surveillance but appears to promote excessive lymphocyte extravasation during inflammatory conditions. Tumor necrosis factor alpha (TNFα) and other inflammatory cytokines increase endothelial MAdCAM-1 expression, and in biopsy specimens from patients with Crohn's disease (CD) and ulcerative colitis (UC), there is a localized increase of approximately two- to three-fold in MAdCAM-1 expression at the site of inflammation. A similar pattern of increased expression has been observed in experimental models of colitis. Other preclinical models of inflammatory conditions, such as insulin-dependent diabetes mellitus, graft-versus-host disease, chronic liver disease, inflammatory encephalopathy, and gastritis, have demonstrated the reawakening of fetal MAdCAM-1 expression and the role of α4β7 in disease pathogenesis. + There is also lymphocyte involvement.

[0083] A recent paper (Graham et al., "Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis", Hepatology, 75(3), 518-30(2022)) confirmed MAdCAM-1 expression in explanted livers from patients undergoing orthotopic liver transplantation for chronic liver disease (CLD). Hepatic MAdCAM-1 immunopositivity has been reported in over 75% of CLD patients, regardless of etiology or disease severity, and is almost universal in late-stage CLD cases. CD4 α4β7 and CC chemokine receptor type 9 (CCR9) expressing MAdCAM-1 are also involved in the MAdCAM-1 immunoreactivity. +Increased expression of both CCL25 and MAdCAM-1, which may induce tissue infiltration of T cells and a concomitant decrease in peripheral blood frequency (Graham et al. 2022), was present across all CLD groups compared with normal liver. The authors also found that α4β7 expression in the liver was significantly elevated. + CD4 + Increased number of T-effector memory cells, E4β7 + CD8 + The increase in cells and these β7 + We also found that the cells exhibited an increased pro-inflammatory phenotype. These findings were independent of the pathogenesis of liver disease, consistent with the study by Grant et al. (Grant et al., "MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease)", Hepatology, 33(5), 1065-1072 (2001)).

[0084] The abnormal expression of MAdCAM-1 in the liver appears to be functional. Proinflammatory lymphocytes in the liver of PSC patients were primarily non-activated memory T lymphocytes, a significant proportion of which expressed the co-receptors α4β7 and / or CCR9 (Ponsioen et al., "Immunohistochemical analysis of inflammation in primary sclerosing cholangitis", Eur. J. Gastroenterol. Hepatol', 11(7), 769-74 (1999)).

[0085] Medication regimen The present invention relates to dosing regimens for administering MAdCAM-1 antibodies to patients susceptible to or diagnosed with NASH. In one aspect, the invention provides methods for treating patients susceptible to or diagnosed with NASH, comprising administering to the patient a therapeutic amount of about 20 mg to about 150 mg of a MAdCAM-1 antibody. In some embodiments, the method further comprises administering subsequent doses of the MAdCAM-1 antibody.

[0086] In some embodiments, the therapeutic amount of a MAdCAM-1 antibody has a lower limit of 1 mg, 2 mg, 2.25 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg and an upper limit of 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, The dose ranges are 55 mg, 60 mg, 65 mg, 70 mg, less than 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.

[0087] In some embodiments, the subsequent doses of MAdCAM-1 antibody have a lower limit of 1 mg, 2 mg, 2.25 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg and an upper limit of 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, The dose ranges are 55 mg, 60 mg, 65 mg, 70 mg, less than 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.

[0088] In some embodiments, either or both of the therapeutic and subsequent doses of MAdCAM-1 antibody are administered in the range of about 20 mg to about 125 mg. In some embodiments, either or both of the therapeutic and subsequent doses of MAdCAM-1 antibody are administered in the range of about 22.5 mg to about 120 mg. In some embodiments, either or both of the therapeutic and subsequent doses of MAdCAM-1 antibody are administered in the range of about 25 mg to about 150 mg. In some embodiments, either or both of the therapeutic and subsequent doses of MAdCAM-1 antibody are administered in the range of about 25 mg to about 115 mg. In some embodiments, either or both of the therapeutic and subsequent doses of MAdCAM-1 antibody are administered in the range of about 30 mg to about 110 mg. In some embodiments, either or both of the therapeutic and subsequent doses of MAdCAM-1 antibody are administered in the range of about 35 mg to about 105 mg. In some embodiments, either or both of the therapeutic dose and subsequent doses of MAdCAM-1 antibody are administered in the range of about 40 mg to about 100 mg. In some embodiments, either or both of the therapeutic dose and subsequent doses of MAdCAM-1 antibody are administered in the range of about 45 mg to about 95 mg. In some embodiments, either or both of the therapeutic dose and subsequent doses of MAdCAM-1 antibody are administered in the range of about 50 mg to about 90 mg. In some embodiments, either or both of the therapeutic dose and subsequent doses of MAdCAM-1 antibody are administered in the range of about 55 mg to about 85 mg. In some embodiments, either or both of the therapeutic dose and subsequent doses of MAdCAM-1 antibody are administered in the range of about 60 mg to about 80 mg. In some embodiments, either or both of the therapeutic dose and subsequent doses of MAdCAM-1 antibody are administered in the range of about 65 mg to about 75 mg.

[0089] In some embodiments, either or both of the therapeutic dose and the subsequent dose of MAdCAM-1 antibody are administered at about 22.5 mg or about 75 mg.

[0090] In some embodiments, the therapeutic amount of MAdCAM-1 antibody is administered at about 22.5 mg or about 75 mg. In some embodiments, the therapeutic amount of MAdCAM-1 antibody is administered at about 22.5 mg. In some embodiments, the therapeutic amount of MAdCAM-1 antibody is administered at about 75 mg.

[0091] In some embodiments, the subsequent dose of MAdCAM-1 antibody is administered at about 22.5 mg or about 75 mg. In some embodiments, the subsequent dose of MAdCAM-1 antibody is administered at about 22.5 mg. In some embodiments, the subsequent dose of MAdCAM-1 antibody is administered at about 75 mg.

[0092] In some embodiments, either or both of the therapeutic dose and the subsequent dose of MAdCAM-1 antibody are administered at about 25 mg or about 75 mg or about 150 mg.

[0093] In some embodiments, either or both of the therapeutic dose and the subsequent dose of the MAdCAM-1 antibody are administered at about 25 mg.

[0094] In some embodiments, either or both of the therapeutic dose and the subsequent dose of the MAdCAM-1 antibody are administered at about 75 mg.

[0095] In some embodiments, either or both of the therapeutic dose and the subsequent dose of the MAdCAM-1 antibody are administered at about 150 mg.

[0096] In some embodiments, the therapeutic amount of MAdCAM-1 antibody is administered at about 25 mg or about 75 mg or about 150 mg.

[0097] In some embodiments, the therapeutic amount of a MAdCAM-1 antibody is administered at about 25 mg.

[0098] In some embodiments, the therapeutic amount of MAdCAM-1 antibody is administered at about 75 mg.

[0099] In some embodiments, the therapeutic amount of MAdCAM-1 antibody is administered at about 150 mg.

[0100] In some embodiments, the subsequent dose of MAdCAM-1 antibody is administered at about 25 mg.

[0101] In some embodiments, the subsequent dose of MAdCAM-1 antibody is administered at about 75 mg.

[0102] In some embodiments, the subsequent dose of MAdCAM-1 antibody is administered at about 150 mg.

[0103] In some embodiments, the methods of the invention further provide for the administration of subsequent doses of the antibody in amounts about the same as or less than the initial dose.

[0104] In some embodiments, either or both of the therapeutic dose and the subsequent dose of the MAdCAM-1 antibody are administered at a dose of 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.33 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, or 10 mg / kg of patient body weight. In one trial phase, patients receive intravenous administration of the MAdCAM-1 antibody at a dose of 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.33 mg / kg, 1.0 mg / kg, 0.2 mg / kg, 3.0 mg / kg, or 10 mg / kg of patient body weight. In another trial phase, patients receive subcutaneous administration of the MAdCAM-1 antibody at a dose of 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.33 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, or 10 mg / kg of patient body weight. In one phase of the trial, MAdCAM-1 antibodies are administered intravenously at doses of 0.03 mg, 0.1 mg, 0.3 mg, 0.33 mg, 1 mg, 2 mg, and 10 mg per kg of patient body weight.

[0105] Dosage interval In some embodiments, the subsequent dose is administered about 1 to about 12 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 1 to about 52 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 1 to about 72 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 1 to about 104 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered up to 3 to 5 years after the therapeutic dose. In some embodiments, the subsequent dose is administered up to 3 to 5 years. In some embodiments, the subsequent dose is provided about 4 weeks after the therapeutic dose.

[0106] In some embodiments, the subsequent dose is administered about 4 to about 12 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 2 to about 8 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 2 to about 10 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 4 to about 10 weeks after the therapeutic dose. In some embodiments, the subsequent dose is administered about 4 weeks after the therapeutic dose.

[0107] In some embodiments, the subsequent dose is administered about 1 to about 3 months after the therapeutic dose. In some embodiments, the subsequent dose is administered at intervals of about 1 month. In some embodiments, the subsequent dose is administered about 2 months after the therapeutic dose.

[0108] In some embodiments, the MAdCAM-1 antibody is administered every 2 weeks for 52 weeks. In some embodiments, the MAdCAM-1 antibody is administered every 4 weeks for 52 weeks. In some embodiments, the MAdCAM-1 antibody is administered every 6 weeks for 52 weeks.

[0109] In some embodiments, the MAdCAM-1 antibody is administered every 2 weeks for 72 weeks. In some embodiments, the MAdCAM-1 antibody is administered every 4 weeks for 72 weeks. In some embodiments, the MAdCAM-1 antibody is administered every 6 weeks for 72 weeks.

[0110] In some embodiments, the MAdCAM-1 antibody is administered every 2 weeks for 104 weeks. In some embodiments, the MAdCAM-1 antibody is administered every 4 weeks for 104 weeks. In some embodiments, the MAdCAM-1 antibody is administered every 6 weeks for 104 weeks.

[0111] In some embodiments, the MAdCAM-1 antibody is administered every 2 weeks for 3-5 years. In some embodiments, the MAdCAM-1 antibody is administered every 4 weeks for 3-5 years. In some embodiments, the MAdCAM-1 antibody is administered every 6 weeks for 3-5 years.

[0112] In some embodiments, the MAdCAM-1 antibody is administered every 2 weeks indefinitely. In some embodiments, the MAdCAM-1 antibody is administered every 4 weeks indefinitely. In some embodiments, the MAdCAM-1 antibody is administered every 6 weeks indefinitely.

[0113] MAdCAM-1 antibody The present invention relates generally to MAdCAM-1 antibodies and their use in treating patients susceptible to or diagnosed with NASH, including, but not limited to, those listed in Table 2 below.

[0114] [Table 2]

[0115] [Table 3-1]

[0116] [Table 3-2]

[0117] [Table 3-3]

[0118] [Table 3-4]

[0119] [Table 3-5]

[0120] [Table 3-6]

[0121] [Table 3-7]

[0122] [Table 3-8]

[0123] The deposit was made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and the Regulations Thereunder (Budapest Treaty), which ensures maintenance of a viable culture of the deposit for a period of 30 years from the date of deposit. The deposit will be made available by ECACC in accordance with the terms of the Budapest Treaty and is subject to an agreement between Pfizer Inc. and ECACC assuring perpetual and unlimited public availability of the progeny of the culture of the deposit upon the issuance of the relevant U.S. patent or upon the public disclosure of any U.S. or foreign patent application, whichever occurs first, and assuring availability of the progeny to any person determined by the Director of the U.S. Patent and Trademark Office to be entitled thereto in accordance with 35 U.S.C. 122 and Director's regulations thereunder (37 C.F.R. 1.14, including, inter alia, with respect to 886 OG 638).

[0124] The assignee of the present application has agreed that if a culture of the deposited material dies or is lost or killed when cultured under suitable conditions, the material will be promptly replaced in an identical form upon notification. The availability of the deposited material shall not be construed as a license to practice the invention in contravention of rights granted under its authority pursuant to the patent laws of any government.

[0125] Therapeutic Methods of the Present Invention In some embodiments, the antibody is mAb7.16.6 (listed in Table 2), or a variant thereof. In some embodiments, the MAdCAM-1 antibody comprises the CDRs of SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the MAdCAM-1 antibody comprises SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the MAdCAM-1 antibody comprises the CDRs of SEQ ID NO:3 and SEQ ID NO:4. In some embodiments, the MAdCAM-1 antibody comprises the variable domains of SEQ ID NO:3 and SEQ ID NO:4, which are further characterized in Table 4 provided herein below.

[0126] [Table 4]

[0127] The MAdCAM-1 antibodies described herein in Tables 2, 3, and 4 are also described in WO2016 / 110806 (incorporated herein by reference). Among other details, methods for making MAdCAM-1 antibodies and their further characterization are provided in WO2005 / 067620 and WO2019 / 014572 (incorporated herein by reference).

[0128] In some embodiments, alternative MAdCAM-1 antibodies for use in the methods and compositions of the invention may be used.

[0129] Exemplary MAdCAM-1 antibodies are listed in Tables 1 and 2 of WO2005 / 067620, which is incorporated herein by reference. The Examples of WO2005 / 067620 fully describe the antibodies listed in Tables 1 and 2 of the International Patent Publication, and provide characterization information, such as binding affinity, K on , K. off , K. d etc. details are provided.

[0130] In some embodiments, the antibody can be a MAdCAM-1 antibody that cross-competes with an antibody comprising SEQ ID NOs: 1 and 2.

[0131] In some embodiments, an antibody of the invention has one or more of the following characteristics: Half-life in human patients is 20-60 days, Subcutaneous (SC) bioavailability of at least 50%, and / or ●K d is less than 10nM.

[0132] In some embodiments, the antibody may have a half-life in a human patient of at least 30 days. In some embodiments, the antibody may have a half-life in a human patient of at least 35 days. In some embodiments, the antibody may have a half-life in a human patient of at least 40 days. In some embodiments, the antibody may have a half-life in a human patient of at least 45 days. In some aspects, the antibody may have a half-life in a human patient of at least 50 days.

[0133] In some embodiments, the SC bioavailability of the antibody may be at least 60%. In some embodiments, the SC bioavailability of the antibody may be at least 65%. In some embodiments, the SC bioavailability of the antibody may be at least 70%. In some embodiments, the SC bioavailability of the antibody may be at least 75%. In some embodiments, the SC bioavailability of the antibody may be at least 80%. In some embodiments, the SC bioavailability of the antibody may be at least 85%. In some embodiments, the SC bioavailability of the antibody may be at least 90%. In some embodiments, the SC bioavailability of the antibody may be at least 95%. In some embodiments, the SC bioavailability of the antibody may be at least 90%. In some embodiments, the SC bioavailability of the antibody may be at least 99%.

[0134] In some embodiments, the KD is measured by surface plasmon resonance. In some embodiments, surface plasmon resonance can be measured using a Biocore. In some embodiments, SPR can be measured using a Biacore with captured antibody and solution-phase MAdCAM-1.

[0135] In some embodiments, the antibody d In some embodiments, the antibody has a K d In some embodiments, the antibody has a K d In some embodiments, the antibody has a K d In some embodiments, the antibody has a K d In some embodiments, the antibody has a K d In some embodiments, the antibody has a K d In some embodiments, the antibody has a K d In some embodiments, the antibody has a Kd is less than 5 pM.

[0136] Pharmaceutical Compositions and Administration MAdCAM-1 antibodies and their antigen-binding portions can be incorporated into pharmaceutical compositions suitable for administration to patients. Typically, pharmaceutical compositions comprise a MAdCAM-1 antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Some examples of pharmaceutically acceptable carriers include water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it will be preferable to include isotonic agents, such as sugars, polyalcohols (such as mannitol, sorbitol), or sodium chloride in the composition. Further examples of pharmaceutically acceptable substances are wetting agents or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the antibody.

[0137] The compositions of the present invention may be in a variety of forms, such as liquids, semi-solids, and solids, such as solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The forms vary depending on the intended method of administration and therapeutic use. Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans. In some cases, the method of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In other cases, antibodies are administered by intravenous infusion or injection. In other cases, antibodies are administered by intramuscular or subcutaneous injection. Injectable formulations may be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with or without added preservatives. The compositions may be in such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Sterile injectable solutions can be prepared by incorporating the required amount of MAdCAM-1 antibody in an appropriate solvent with one or a combination of the above-listed ingredients, as required, followed by filtered sterilization.

[0138] The dosage value varies depending on the type and severity of the condition to be alleviated. In the case of sterile powders for the preparation of sterile injectable solutions, suitable methods of preparation include vacuum drying and freeze-drying, which yield powders from a previously sterile-filtered solution of the active ingredient to which any desired additional ingredients are added. The proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

[0139] In some cases, MAdCAM-1 antibodies can be prepared with carriers that protect the antibody against rapid release, such as controlled-release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods can be used to prepare such formulations. See, for example, "Sustained and Controlled Release Drug Delivery Systems," J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978, incorporated herein by reference.

[0140] Additional active compounds can be incorporated into the composition (including any one or more of the additional therapeutic agents disclosed above). In some cases, the inhibitory MAdCAM-1 antibody is combined with and / or co-administered with one or more additional therapeutic agents. These agents include, but are not limited to, antibodies that bind to other targets, anti-tumor agents, anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, chemotherapeutic agents, or peptide analogs that inhibit MAdCAM-1. Such combination therapy may require lower dosages of the inhibitory MAdCAM-1 antibody and the co-administered agents, thus avoiding potential toxicities or complications associated with various monotherapies.

[0141] In some embodiments, the patient is not taking a tumor necrosis factor (TNF) antagonist or TNF inhibitor.

[0142] The compositions may include a "therapeutically effective amount" or a "prophylactically effective amount" of an antibody or antigen-binding portion. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of an antibody or antigen-binding portion may vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or adverse effects of the antibody or antigen-binding portion are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, a prophylactic dose is used in patients prior to or at an earlier stage of disease, so the prophylactically effective amount may be less than the therapeutically effective amount.

[0143] In some embodiments, the MAdCAM-1 antibody is administered in a formulation as a sterile aqueous solution having a pH ranging from about 5.0 to about 6.5, about 1 mM to about 100 mM histidine buffer, about 0.01 mg / mL to about 10 mg / mL polysorbate 80 or polysorbate 20, about 100 mM to about 400 mM non-reducing sugar (selected from, but not limited to, trehalose or sucrose), about 0.01 mM to about 1.0 mM disodium EDTA dihydrate, and optionally a chelating agent and a pharmaceutically acceptable antioxidant. Suitable antioxidants include, but are not limited to, methionine, sodium thiosulfate, catalase, and platinum.

[0144] In some embodiments, the formulation is as described in WO2006 / 096490, the contents of which are incorporated herein. In some embodiments, the formulation comprises 75 mg / mL antibody, 10 mM histidine (pH 5.5), 90 mg / mL trehalose (dihydrate), 0.1 mg / mL disodium EDTA dihydrate, and 0.4 mg / mL polysorbate 80.

[0145] In another embodiment, the formulation comprises 20 mM histidine, 7% trehalose, 0.4 mg / mL polysorbate 80, 0.1 mg / mL EDTA, pH 5.5, and 25 mg / mL and 75 mg / mL anti-MAdCAM-1 antibody.

[0146] In some embodiments, the present invention provides a method for treating a patient susceptible to or diagnosed with NASH, comprising administering a therapeutic amount of a MAdCAM-1 antibody to the patient, wherein the MAdCAM-1 antibody is administered subcutaneously to the patient.

[0147] In some embodiments, the present invention provides a method for treating a patient susceptible to or diagnosed with NASH, comprising administering a therapeutic amount of a MAdCAM-1 antibody to the patient, wherein the MAdCAM-1 antibody is administered intravenously to the patient.

[0148] The MAdCAM-1 antibody may also be administered continuously via a minipump. The MAdCAM-1 antibody may be administered via mucosal, buccal, intranasal, inhalable, intravenous, subcutaneous, intramuscular, parenteral, or intratumoral routes. The MAdCAM-1 antibody may be administered once, at least twice, or for at least as long as necessary to treat, alleviate, or cure the condition. The MAdCAM-1 antibody is generally administered for as long as the condition exists.

[0149] In one aspect, the invention provides the use of a MAdCAM-1 antibody for the manufacture of a medicament for the retreatment of NASH.

[0150] In one aspect, the invention provides a MAdCAM-1 antibody for use in treating NASH.

[0151] Diagnosis and evaluation of NASH In one aspect, the present invention provides a method for assessing whether a patient has a beneficial response after subcutaneous administration of a MAdCAM-1 antibody at a dose of 22.5 mg, 25 mg, 75 mg, or 150 mg to patients with non-alcoholic steatohepatitis (NASH) at different stages of liver fibrosis, comprising: (a) measuring the level of a biomarker in a biological sample from the patient, wherein the biomarker is (i) neoepitope-specific type III collagen N-terminal propeptide (Pro-C3) and (ii) enhanced liver fibrosis (ELF); and (b) comparing the level with a control, wherein a change in the level of the biomarker compared to the control predicts a beneficial response in the patient.

[0152] In some embodiments, NASH can be diagnosed by liver biopsy (e.g., histological evidence of, e.g., steatosis, inflammation, and hepatocellular ballooning, in the absence of other causes of liver disease or heavy alcohol consumption). For example, the NAFLD Activity Score (NAS) can be useful in identifying patients with NASH. See Kleiner et al., "Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease," Hepatology, 41(6):1313-1321 (2005).

[0153] The NAS is the sum of the individual scores for steatosis (0-3), hepatocellular ballooning (0-2), and lobular inflammation (0-3), with a maximum score of 8. The NAS score can be generated at the time of biopsy according to the criteria described in Kleiner et al., supra. See also Table 5.

[0154] [Table 5]

[0155] In some embodiments, patients are selected based on a liver biopsy (eg, the liver biopsy used to determine the NAS score).

[0156] In some embodiments, patients are selected based on their NAS score. In some embodiments, the presence of NASH is determined by an NAS score of 2 or greater and 3 or less (i.e., an NAS score of 2-3). In some embodiments, the presence of NASH is determined by an NAS score of 4 or greater (i.e., an NAS score of 4 or greater). In some embodiments, the presence of NASH can be determined by a liver biopsy revealing an NAS score of 5 or greater (i.e., an NAS score of 5 or greater).

[0157] In some embodiments, patients are selected based on a NAS score determined prior to treatment.

[0158] In some embodiments, the presence of NASH is determined by an NAS score of 2 or greater and 3 or less (i.e., an NAS score of 2-3). In some embodiments, the presence of NASH is determined by a pre-treatment NAS score of 4 or greater (i.e., an NAS score of 4 or greater). In some embodiments, the presence of NASH may be determined by a liver biopsy revealing a pre-treatment NAS score of 5 or greater (i.e., an NAS score of 5 or greater).

[0159] In some embodiments, NASH may be characterized by a NAFLD Activity Score (NAS) of 5 or greater, where NAS is the sum of the individual scores for steatosis (range: 0-3), hepatocellular ballooning (range: 0-2), and lobular inflammation (range: 0-3). See Kleiner et al. (supra). Steatosis is the abnormal accumulation of lipids within the liver. The steatosis score represents the percentage (%) of hepatocytes containing lipid droplets (steatosis) as 0 (less than 5%), 1 (5-33%), 2 (33-66%), and 3 (more than 66%). Patients treated for NASH according to the present disclosure may have a NAS steatosis score of 1, 2, or 3. Hepatocellular ballooning is a type of cell death visually characterized by enlargement and localization of the cell nucleus at or near the center of the cell. In some embodiments, hepatocellular ballooning is scored as 0 (none), 1 (few), or 2 (many cells with significant ballooning). In some embodiments, lobular inflammation is scored according to the number of inflammatory foci: 0 (no foci), 1 (fewer than 2 foci / 200x field), and 2 (2-4 foci / 200x field). In some embodiments, patients have a lobular inflammation score of 0, 1, 2, or 3 and a ballooning score of 0, 1, or 2, provided that the sum of the lobular inflammation score and ballooning score is at least 2.

[0160] In some embodiments, the methods and uses described herein comprise an improvement in NAS score. In some embodiments, the improvement occurs without a worsening of fibrosis.

[0161] In some embodiments, administration of the MAdCAM-1 antibody results in a NAFLD Activity Score (NAS) of less than 4.

[0162] In some embodiments, the methods and uses described herein result in a decrease in the patient's NAS score of at least 1 (1 or greater).

[0163] In some embodiments, the methods and uses described herein result in a reduction in the patient's NAS score of at least 2 (2 or greater).

[0164] In some embodiments, the methods and uses described herein result in a reduction in the patient's NAS score of at least 3 (3 or greater).

[0165] In some embodiments, the methods and uses described herein result in a reduction of 1-3 in a patient's steatosis score.

[0166] In some embodiments, the methods and uses described herein result in a decrease of 1 or 2 in a patient's hepatocellular ballooning score.

[0167] In some embodiments, the methods and uses described herein result in a reduction of 1-3 in the patient's lobule inflammation score.

[0168] In some embodiments, the patient has a steatosis score of 1, 2, or 3.

[0169] In some embodiments, the steatosis comprises macrovesicular steatosis. In some embodiments, the steatosis comprises microvesicular steatosis. In some embodiments, the steatosis comprises macrovesicular and microvesicular steatosis.

[0170] In some embodiments, the methods and uses described herein result in the resolution of steatohepatitis without worsening fibrosis in a patient in need thereof. In some embodiments, resolution includes the absence of hepatocellular ballooning (e.g., a ballooning score of 0); absence or mild inflammation (e.g., a ballooning score of 0-1); and / or the presence or absence of steatosis (e.g., a steatosis score of 0-3).

[0171] In some embodiments, NASH is steatohepatitis characterized by at least one of lobular inflammation and hepatocellular ballooning. In some embodiments, NASH occurs in the absence of other causes of liver disease and / or heavy alcohol intake.

[0172] In some embodiments, the patient has liver inflammation, hi some embodiments, the liver inflammation is lobular inflammation.

[0173] In some embodiments, administering a MAdCAM-1 antibody results in a decrease in liver inflammation.

[0174] In some embodiments, administration of a MAdCAM-1 antibody results in a liver inflammation score of 0 or 1 (eg, as described herein).

[0175] In some embodiments, the patient's liver is characterized by hepatocellular ballooning.

[0176] In some embodiments, administering a MAdCAM-1 antibody results in a reduction in hepatocellular ballooning.

[0177] In some embodiments, administration of a MAdCAM-1 antibody results in a ballooning score of 0.

[0178] In some embodiments, treatment is initiated independent of determining the NAS score.

[0179] In some embodiments, the methods and uses described herein result in an improvement in NAS of at least 2 points without worsening fibrosis in a patient in need thereof.

[0180] In some embodiments, the patient has liver fibrosis.

[0181] In some embodiments, fibrosis is scored / staged on a scale of 0 to 4 (Table 6 below).

[0182] [Table 6]

[0183] In some embodiments, the patient has non-cirrhotic NASH.

[0184] In some embodiments, the patient has cirrhotic NASH.

[0185] In some embodiments, the patient has compensated cirrhotic NASH.

[0186] In some embodiments, the patient has a fibrosis stage score of 0 to 3. In embodiments, the patient has a fibrosis stage score of 0. In some embodiments, the patient has a fibrosis stage score of 1. In some embodiments, the patient has a fibrosis stage score of 2. In some embodiments, the patient has a fibrosis stage score of 3. In some embodiments, the patient has a fibrosis stage score of 4 (cirrhosis). In some embodiments, the patient after treatment may have a fibrosis stage score that is at least no worsening from the pre-treatment baseline score, or in other cases, the fibrosis stage score may be reduced by at least 1 level, or alternatively by at least 2 or 3 levels.

[0187] In some embodiments, the methods and uses described herein do not result in an increase in the patient's liver fibrosis score (stabilization of the patient's liver fibrosis).

[0188] In some embodiments, the methods and uses described herein result in a reduction in the patient's liver fibrosis score by at least 1 (greater than or equal to 1) (reversal of liver fibrosis in the patient).

[0189] In some embodiments, liver fibrosis is characterized using an Enhanced Liver Fibrosis Test (ELF) score. In some embodiments, liver fibrosis is characterized by an ELF score of less than 7.7. In some embodiments, liver fibrosis is characterized by an ELF score of 7.7 or greater but less than 9.8. In some embodiments, liver fibrosis is characterized by an ELF score of greater than 9.8.

[0190] In some embodiments, the methods and uses described herein result in maintenance of fibrosis stage (no progression) in patients in need thereof.

[0191] In some embodiments, the methods and uses described herein result in regression of fibrosis in a patient in need thereof.

[0192] In some embodiments, the methods and uses described herein result in a reduction in liver enlargement in a patient.

[0193] In some embodiments, the methods and uses described herein reduce collagen levels in the patient's liver.

[0194] In some embodiments, the methods and uses described herein reduce alpha smooth muscle actin (α-SMA) levels in liver tissue of a patient.

[0195] In some embodiments, the methods and uses described herein reduce the level of hepatocyte apoptosis in a patient.

[0196] In some embodiments, the methods and uses described herein result in a reduction in hyaluronic acid levels in a patient.

[0197] In some embodiments, the methods and uses described herein reduce tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in a patient.

[0198] In some embodiments, the methods and uses described herein result in a reduction in the level of procollagen type III terminal peptide (PIIINP) in a patient.

[0199] In some embodiments, the methods and uses described herein result in a reduction in soluble Fas ligand levels in a patient.

[0200] In some embodiments, the methods and uses described herein reduce leptin levels in a patient.

[0201] In some embodiments, the methods and uses described herein result in a decrease in the aspartate aminotransferase (AST) to platelet index (APRI) in a patient.

[0202] In some embodiments, the methods and uses described herein result in a reduction in a patient's Fibrosis 4 (FIB-4) score.

[0203] In some embodiments, the methods and uses described herein result in a reduction in liver stiffness in a patient.

[0204] In some embodiments, the methods and uses described herein increase adiponectin levels in a patient.

[0205] In some embodiments, the methods and uses described herein reduce neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3) levels in a patient.

[0206] In some embodiments, the methods and uses described herein result in a reduction in soluble MAdCAM-1 levels in a patient.

[0207] In some embodiments, the methods and uses described herein result in a reduction in high sensitivity C-reactive protein (hsCRP) levels in a patient.

[0208] In some embodiments, the methods and uses described herein result in a reduction in calprotectin levels in a patient.

[0209] In some embodiments, the methods and uses described herein result in a reduction in interleukin 8 (IL-8) levels in a patient.

[0210] Serum markers and biomarkers In some embodiments, any of the methods and uses described herein results in a change in a serum marker (e.g., a serum marker of a liver pathology such as liver fibrosis or NASH) in a patient in need thereof. Thus, in embodiments, patients are selected based on a particular expression level of a serum marker (including any described herein). For example, the methods described herein may be particularly beneficial for patients with a particular (e.g., threshold level) of a serum marker (e.g., any described herein). Furthermore, the methods described herein may result in a favorable change in the serum marker (e.g., may modulate the level of any serum marker described herein). In some embodiments, the methods described herein may result in a decrease in an elevated serum marker (e.g., any described herein).

[0211] For example, noninvasive measures of fibrosis for monitoring treatment efficacy can be useful to avoid the need for repeat liver biopsies (e.g., to identify patients who could benefit from the methods described herein, including patients with any of the liver pathologies described herein, such as NASH). In some embodiments, the serum marker is FIB-4. In some embodiments, the serum marker is APRI. APRI and FIB-4 scores can be calculated using the following published formula (Kim et al., "Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States," Hepatology, 57:1357 (2013)), where "PLT count" is the platelet count, "AST" is aspartate transaminase, with an upper limit of normal of 40 IU / mL, and "ALT" is alanine aminotransferase: APRI = ([AST / upper limit of normal] / PLT count [109 / L]) FIB-4 = (age [years] × AST [IU / L]) / (PLT [109 / L] × (ALT [IU / L]) 1 / 2).

[0212] Thus, exemplary serum markers include enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or gamma-glutamyltransferase (GGT), or any combination thereof. In embodiments, the patient has elevated levels of at least one liver enzyme.

[0213] Still other exemplary serum markers include total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, bilirubin, albumin, C-peptide, apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin, and tumor necrosis factor-alpha (TNF-α).

[0214] In some embodiments, the patient has elevated liver alanine aminotransferase (ALT) levels. In some embodiments, the methods and uses described herein result in a decrease in liver alanine aminotransferase (ALT) levels. In some embodiments, the patient has ALT levels within normal limits (e.g., about 10-40 IU / L). In some embodiments, the patient has ALT levels greater than about 40 IU / L. In some embodiments, the ALT is less than or equal to about 30 IU / L (e.g., for male patients). In some embodiments, the ALT is greater than about 30 IU / L (e.g., for male patients). In some embodiments, the ALT is less than or equal to about 19 IU / L (e.g., for female patients). In some embodiments, the ALT is greater than about 19 IU / L (e.g., for female patients).

[0215] In some embodiments, the patient has elevated hepatic aspartate aminotransferase (AST) levels. In some embodiments, the patient has AST levels within normal limits (e.g., between about 10 and 35 IU / L). In some embodiments, the patient has AST levels greater than about 30 IU / L. In some embodiments, the patient has AST levels greater than about 35 IU / L. In embodiments, the methods and uses described herein result in a reduction in hepatic aspartate aminotransferase (AST) levels.

[0216] In some embodiments, the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (AST) is determined. In some embodiments, the patient has an AST / ALT ratio greater than 1. In some embodiments, the patient has an AST / ALT ratio less than 1.

[0217] In some embodiments, the methods and uses described herein result in a decrease in the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) in a patient.

[0218] In some embodiments, the methods and uses described herein result in a change in the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) in a patient, such that the ratio is closer to 1.

[0219] In some embodiments, the patient has elevated alkaline phosphatase (ALP) levels. In some embodiments, the patient has ALP levels within the normal range (e.g., about 20-140 or about 37-116 IU / L). In some embodiments, the patient has ALP levels greater than about 120 IU / L or about 140 IU / L. In some embodiments, the patient has ALP levels greater than about 150 IU / L. In some embodiments, the methods and uses described herein result in a decrease in alkaline phosphatase (ALP) levels.

[0220] In some embodiments, the patient has elevated gamma-glutamyltransferase (GGT) levels. In some embodiments, the patient has GGT levels within the normal range (e.g., about 5-30 IU / L or about 9-48 IU / L). In some embodiments, the patient has GGT, and in some embodiments, the patient has elevated GGT levels, at least about 50 IU / L. In some embodiments, the GGT levels are up to about 90 IU / L or about 100 IU / L. In some embodiments, the methods and uses described herein result in a decrease in GGT levels.

[0221] In some embodiments, the patient has elevated triglyceride levels. In some embodiments, the methods and uses described herein result in a reduction of triglyceride levels.

[0222] In some embodiments, the patient has elevated free fatty acid (NEFA) levels. In some embodiments, the methods and uses described herein result in a decrease in free fatty acid (NEFA) levels.

[0223] In some embodiments, the patient has elevated cholesterol levels. In some embodiments, the methods and uses described herein result in a reduction of cholesterol levels.

[0224] In some embodiments, the patient has reduced HDL cholesterol levels.

[0225] In some embodiments, patients are selected based on their Child-Pugh score, which is determined based on total bilirubin (TBL), serum albumin, internal normalized ratio (INR), the degree of ascites, and the degree of hepatic encephalopathy.

[0226] In some embodiments, patients are selected based on multiparametric magnetic resonance imaging: iron-corrected T1.

[0227] In some embodiments, patients are selected based on their Model for End Stage Liver Disease (MELD) score. The MELD score is determined based on the INR of serum bilirubin, serum creatinine, and prothrombin. In some embodiments, the MELD score is less than 12. In some embodiments, the MELD score is 12 or greater. In some embodiments, the MELD score is 15 or greater.

[0228] In some embodiments, patients are selected based on the West Haven criteria (WHC) for hepatic encephalopathy.

[0229] In some embodiments, the surrogate marker is selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST), controlled attenuation parameter (CAP), enhanced liver fibrosis test (ELF), fibrosis stage (F), FibroScan-aspartate aminotransferase (FAST), fibrosis-4 index (FIB-4), formalin-fixed paraffin-embedded (FFPE), high-sensitivity C-reactive protein (hsCRP), interleukin (IL), liver stiffness measurement (LSM), and neoepitope-specific N-terminal propeptide of type III collagen (Pro C3).

[0230] In some embodiments, the marker is selected from Pro-C, ELF, soluble MAdCAM-1, hsCRP, calprotectin, IL-8, and blood T cell phenotyping.

[0231] In some embodiments, the surrogate marker (e.g., biomarker) is selected from markers of circulating blood cell populations. In some embodiments, the marker includes a marker for Th17 / Th1 cells. In some embodiments, the marker includes a marker for Th2 cells. In some embodiments, the marker includes β7 + Markers for T cells are included. In some embodiments, the markers include CCR9. In some embodiments, the markers include CXCR3.

[0232] In some embodiments, cirrhosis is characterized using the Agile4 score, which is a derived score that takes into account LSM, AST, ALT, platelets, diabetic status, and gender.

[0233] Liver inflammation In one aspect, the invention features a method for treating (e.g., reducing) liver inflammation, the method comprising administering to a patient in need thereof an effective amount of a MAdCAM-1 antibody.

[0234] In some embodiments, the liver inflammation is lobular inflammation.

[0235] Hepatocellular ballooning In one aspect, the invention features a method for treating (e.g., reducing) hepatocellular ballooning, the method comprising administering to a patient in need thereof an effective amount of a MAdCAM-1 antibody.

[0236] Hepatocellular ballooning is a type of cell death that is visually characterized by enlargement and localization of the cell nucleus at or near the center of the cell.

[0237] In some embodiments, administration of a MAdCAM-1 antibody results in a ballooning score of 0.

[0238] In some embodiments, the patient has non-alcoholic steatohepatitis (NASH).

[0239] Liver fibrosis (including cirrhosis) In one aspect, the invention features a method for treating liver fibrosis, the method comprising administering to a patient in need thereof an effective amount of a MAdCAM-1 antibody.

[0240] In some embodiments, the patient has stage 2, stage 3, or stage 4 liver fibrosis.

[0241] In some embodiments, the patient has cirrhosis (stage 4 liver fibrosis).

[0242] In some embodiments, the patient has a fibrosis stage score of 1 or greater.

[0243] In some embodiments, the patient has a fibrosis stage score of 0-3.

[0244] In some embodiments, the patient has a fibrosis stage score of 0. In embodiments, the patient has a fibrosis stage score of 1. In embodiments, the patient has a fibrosis stage score of 2. In embodiments, the patient has a fibrosis stage score of 3. In embodiments, the patient has a fibrosis stage score of 4 (cirrhosis).

[0245] In some embodiments, post-treatment patients may have a fibrosis stage score that is at least no worsening from the pre-treatment baseline score, or in other cases, a decrease in fibrosis stage score of at least one level, or alternatively at least two or three levels.

[0246] fatty degeneration In one aspect, the invention features a method for treating steatosis, the method comprising administering to a patient in need thereof an effective amount of a MAdCAM-1 antibody.

[0247] In some embodiments, administering the MAdCAM-1 antibody results in a reduction in steatosis in the patient.

[0248] In some embodiments, the steatosis comprises macrovesicular steatosis. In embodiments, the steatosis comprises microvesicular steatosis. In embodiments, the steatosis comprises macrovesicular and microvesicular steatosis. [Example]

[0249] Other features, objects, and advantages of the present invention will become apparent in the following examples. However, it should be understood that the examples, while illustrating embodiments of the present invention, are given by way of illustration only, not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the examples.

[0250] Provided herein are clinical trials being conducted to explore the mechanism of action and evaluate the safety and tolerability of MAdCAM-1 antibodies in participants with nonalcoholic steatohepatitis (NASH).

[0251] The clinical trial is designed to explore the role of MAdCAM-1 in NASH by administering a MAdCAM-1 inhibitor (i.e., MAdCAM-1 antibody) and to evaluate the safety and tolerability of a 75 mg dose of the MAdCAM-1 antibody in participants with NASH at various liver fibrosis stages (stages 2-3 and stage 4 / cirrhosis without decompensation) ranging from stage 2 to 4 (nonalcoholic fatty liver disease activity score (NAS) ≥ 4 with at least 1 point each for steatosis, ballooning, and lobular inflammation). The role of MAdCAM-1 will be assessed by changes in inflammatory and fibrotic biomarkers and liver function tests compared to baseline. Multiparametric MRI (cT1) will be used to assess fibroinflammatory changes in the liver.

[0252] Example 1: First Study Design and Methods This clinical trial is a multicenter, single-arm, open-label, Phase 1b study. A schematic diagram of the study design is shown in Figure 1. The clinical trial includes three distinct periods or phases: a screening period, a treatment period, and a safety follow-up period. The screening period spans eight weeks prior to the treatment period. The treatment period begins immediately after the screening period and lasts for 24 weeks, while the follow-up period begins immediately after the treatment period and lasts for 12 weeks. Example 2 below lists and describes the full activity schedule conducted during each period.

[0253] The study will enroll approximately 30 participants to ensure that at least 18 participants (approximately 12 participants in F2 / F3 and approximately 6 participants in F4cc) complete the 24-week treatment period. It is not necessary to enroll F2 and F3 participants in a 1:1 ratio.

[0254] Participants were aged 18 to 70 years and had a diagnosis of NASH without compensated cirrhosis or neoplasia. A broad NASH population was included, including participants with confirmed stable type 2 diabetes mellitus (T2DM) or a body mass index of 25 kg / m. 2Participants with ≥1 metabolic syndrome criterion will be accepted into the study.

[0255] In this study, screening for liver biopsy eligibility was defined by an assessment performed at the first screening visit (week -8), which included circulating biomarkers (e.g., AST), clinical information (e.g., age), imaging data (e.g., liver stiffness measurement (LSM) by FibroScan and liver fat content by controlled attenuation parameter (CAP)), and serum Pro-C3 (neoepitope-specific N-terminal propeptide of type III collagen) levels and the Enhanced Liver Fibrosis (ELF) score (tissue inhibitor of metalloproteinase 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP)). The study included a noninvasive test (i.e., FAST score) combining a steroid hormone (HSH) and hyaluronic acid (HA). Participants with a FAST score >0.35, Pro-C3 >12.6 ng / mL, and ELF score >7.7 (in addition to other inclusion and exclusion criteria such as ALT and AST levels) at Week -8 were eligible for a liver biopsy performed at the Week -6 screening visit. Evidence of NASH (NAS >4 with at least 1 each for steatosis, ballooning, and lobular inflammation) and liver fibrosis stage F2-F4cc on the liver biopsy allowed participants to enroll in the study.

[0256] Previous liver biopsy specimens may be used for screening purposes if they were collected between 24 weeks and 4 weeks before the start of the screening period. For F4 participants who meet the inclusion and exclusion criteria before safety and tolerability are established in the first four F2 / F3 participants, previous liver biopsy specimens may be used for screening purposes if they were collected within 10 weeks before the screening period (the maximum allowable time between the previous biopsy and the first dose of study drug is 34 weeks for any participant). The first screening visit must occur at least 4 weeks after the previous biopsy to ensure that any biopsy-induced changes in liver function parameters or biomarkers have stabilized. If an eligible previous liver biopsy specimen is available for central review and interpretation by the study pathologist and meets all criteria defined in the Histopathology Manual, a repeat liver biopsy is not required during screening. The previous liver biopsy specimen must demonstrate evidence of NASH (NAS score ≥ 4 with at least one score each for steatosis, ballooning, and lobular inflammation) and liver fibrosis stage F2-44cc. Participants with a qualifying prior liver biopsy must have adhered to restrictions regarding prohibited hepatotoxic medications during the specified period prior to the prior liver biopsy sampling. For participants with a qualifying prior liver biopsy, a baseline abdominal MRI visit may occur as soon as possible after the liver chemistry results from Screening Visit 2 are available, with at least 2 weeks separating Screening Visit 2 and the Day -4 visit (Visit 4a2).

[0257] During the screening period, Pro-C3, ELF, and other exploratory markers will be measured at three visits (including pre-dose on Day 1) to determine within-participant variability, allowing for proper interpretation of post-treatment reductions in these biomarkers compared to within-participant variability at baseline.

[0258] Eligible F4cc participants will be enrolled after safety and tolerability have been established in the first four F2 / F3 participants who receive at least three 75 mg doses of the MAdCAM-1 antibody and have been monitored for at least 12 weeks after the first dose. The screening period may be extended to up to 24 weeks for participants whose results are consistent with F4 fibrosis (i.e., compensated cirrhosis) after the initial screening visit (i.e., a combined FIB-4 of 3.48 or greater and an LSM of 20 kPa or greater, or an Agile4 score of 0.57 or greater) or whose screening or prior liver biopsy confirms F4 NASH (NAS 4 or greater with at least 1 each for steatosis, ballooning, and lobular inflammation) until safety and tolerability data have been evaluated in the first four F2 / F3 participants.

[0259] All eligible participants (F2-F4) will enter a 24-week, single-arm, open-label treatment period with 75 mg of anti-MAdCAM-1 antibody. The anti-MAdCAM-1 antibody will be administered subcutaneously (SC) Q4W for 24 weeks (final dose at week 20), followed by a 12-week safety follow-up period. Liver biopsy specimens will be collected at screening and week 24. At the start of the treatment period and week 24, fibroinflammation will be assessed by cT1 MRI, liver stiffness by FibroScan, and hepatocellular function will be assessed by HepQuant-SHUNT DSI (optional if the site is unable to perform this assessment, but not optional for participants if the site is able to perform this assessment). At Q4W visits between baseline and Week 24, assessments of selected biomarkers (including but not limited to Pro-C3, ELF, soluble MAdCAM-1, hsCRP, and calprotectin), liver chemistry tests, and specific safety data collection (laboratory tests, adverse events [AEs], neurological assessment) will be performed. Liver stiffness measurements by FibroScan will also be performed at Week 12. Safety and tolerability data will be continuously monitored and evaluated by an internal group independent of the study team. All participants, including those who discontinue, will be placed in a 12-week safety follow-up period after their final dose of study medication. The end of the study will be defined as the last visit of the last participant on the study (Week 36).

[0260] The maximum length of time a participant will participate in this study is expected to be approximately 46 weeks (11.5 months), except for participants with F4 cirrhosis who met the inclusion and exclusion criteria (described herein) before safety and tolerability was established in the four F2 / F3 participants, for whom the total study duration is expected to be approximately 60 weeks (15 months).

[0261] Example 2: Test Activity Schedule A number of activities will be conducted during the screening, treatment, follow-up and end-of-study periods and are described below under the activity schedule.

[0262] Examination Activity Schedule - Screening Period Table 7 lists the activities that will be performed and / or monitored during the screening period of the study.

[0263] [Table 7-1]

[0264] [Table 7-2]

[0265] [Table 7-3]

[0266] The term "informed consent" indicates that the informed consent process must be completed, signed, and dated before proceeding.

[0267] The term "pregnancy prevention counseling" refers to lifestyle habits, e.g., contraception and breastfeeding restrictions. The term "AE assessment" refers to adverse events that should be collected from the time participants sign the informed consent form.

[0268] Reassessment of AE / SAE. The term "vital signs" refers to vital signs including blood pressure (at rest for more than 5 minutes), pulse rate, respiratory rate, and temperature.

[0269] The term "targeted neurological assessment" indicates that participants will be evaluated to uncover any potential abnormalities in the following neurological domains: vision, motor, tactile, coordination / cerebellar function, speech, language comprehension, and cognitive / behavioral domains. Participants with unexplained positive items during screening suggestive of progressive multifocal leukoencephalopathy (PML) will be excluded.

[0270] The term "chest x-ray" refers to the optional use of a chest x-ray performed within 12 weeks prior to the initial screening visit, if available.

[0271] "Blood sample - clinical chemistry panel" or "blood sample - hematology panel" indicates that laboratory tests such as blood glucose and triglyceride levels are collected in a fasting state.

[0272] "Serologic panel" indicates the panel includes HIV (HIV-Ab / Ag), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis C (HCVAb). Participants who test negative for HBsAg but positive for HBcAb are considered eligible if they have a negative HBV DNA result (confirmed by HBV DNA PCR reflex test). Participants with a positive HBV DNA test result are not eligible. Participants who are HCVAb positive without evidence of HCV RNA may be considered eligible (spontaneous clearance of the virus or previously treated and cured [defined as no evidence of HCV RNA at least 12 weeks prior to baseline]).

[0273] "Infectious Disease Panel" indicates that the infection panel includes cytomegalovirus, Epstein-Barr virus, and herpes simplex virus.

[0274] IGRA screening may be repeated during the screening period if the initial result is inconclusive. Participants may be enrolled if the IGRA confirmation result from the central laboratory is negative. If the IGRA confirmation result is positive, the participant should be screened out. If both the initial and confirmatory IGRA results are inconclusive, participants may be enrolled after a negative Mantoux tuberculin skin test and after consultation with the sponsor and a pulmonary or infectious disease specialist who determines that the risk of infection is low and that there are no risks from immunosuppressive treatment. If the consultation time exceeds the consultation period, the participant should be screened out and may be screened again after the consultation confirms eligibility for study participation. This consultation must be included in the participant's medical history.

[0275] "FSH" indicates that follicle-stimulating hormone is assessed for postmenopausal participants.

[0276] "Serum β-hCG" indicates that pregnancy testing is only applicable to participants of childbearing potential. A confirmatory serum β-hCG pregnancy test is required only for participants with a positive urine pregnancy test at any time point.

[0277] "Liver Biopsy" indicates that eligibility for liver biopsy at week -6 is determined by data generated from the week -8 assessment, i.e., a FAST score of 0.35 or greater, a Pro-C3 level of 12.6 ng / mL or greater, and an ELF score of 7.7 or greater, in addition to other inclusion and exclusion criteria at week -8. Liver chemistry samples at week -8 must be evaluated and eligibility determined, after which a screening liver biopsy can be performed. For participants who meet other eligibility criteria at week -8, if the ALT / AST results at week -8 are greater than 4x the ULN and less than 5x the ULN, the ALT / AST results at week -6 will also be evaluated, after which a liver biopsy and abdominal MRI can be performed.

[0278] "Circulating biomarkers" refers to repeated samples taken at the same time of day throughout screening.

[0279] "Other exploratory blood biomarker sampling" indicates that the exploratory biomarkers include, but are not limited to, markers of circulating blood cell populations such as, but not limited to, Th17 / Th1 vs. Th2, β7+ T cells, CCR9, and CXCR3.

[0280] Activity Schedule - Treatment Period, Follow-up, and End of Study Table 8 lists the activities that will be performed during the treatment, follow-up, and end-of-study periods.

[0281] [Table 8-1]

[0282] [Table 8-2]

[0283] [Table 8-3]

[0284] [Table 8-4]

[0285] [Table 8-5]

[0286] "AE Assessment" indicates that all adverse events will be collected from the time the participant signs the informed consent form.

[0287] "Vital signs" include blood pressure (at rest for more than 5 minutes), pulse rate, respiratory rate, and temperature.

[0288] "Targeted neurological assessment" indicates that participants will be evaluated to uncover any potential abnormalities in the following neurological domains: vision, movement, touch, coordination / cerebellar function, speech, language comprehension, and cognitive / behavioral domains.

[0289] "Laboratory tests" indicates that blood glucose and triglyceride levels are collected in the fasting state.

[0290] A liver biopsy must be performed as the final evaluation at the Week 24 / End of Treatment / Early Discontinuation visit.

[0291] "Urinary β-hCG" indicates that pregnancy testing is only applicable to participants of childbearing potential. A confirmatory serum β-hCG pregnancy test is required only for participants with a positive urine pregnancy test at any time point.

[0292] Whole blood T cell phenotyping will explore biomarkers such as Th17 / Th1 vs. Th2 and β7 + Markers of circulating blood cell populations such as, but not limited to, T cells, CCR9 and CXCR3 are indicated.

[0293] "Administration of MAdCAM-1 antibody" indicates administration of the test drug.

[0294] Hypersensitivity monitoring indicates that participants will be monitored for the presence of Type I (anaphylaxis) and Type III (immune complex) hypersensitivity reactions. Participants experiencing AEs suggestive of Type I and Type III hypersensitivity reactions will have blood samples (3 mL and 4 mL, respectively) collected for determination of anti-MAdCAM IgE antibodies (Type I) and C3a and C5b 9 (Type III), respectively.

[0295] Example 3: Study Population The study population, i.e., participants, will be governed by the exclusion and inclusion criteria provided herein.

[0296] Selection Criteria All participants must meet all of the following criteria to be eligible for the study:

[0297] Participants were between 18 and 70 years old (inclusive) at the time they signed the ICF.

[0298] Participants must have a FAST score of 0.35 or greater (applies to participants without a prior liver biopsy who are eligible at the time of enrollment). For participants with a prior liver biopsy showing evidence of liver fibrosis stage F2, F3, or F4cc according to the NASH CRN, a FAST score of 0.35 or greater at enrollment is not required.

[0299] Participants will have evidence of fibrotic activity (Pro-C3 >12.6 ng / mL, ELF score ≥7.7) at the week -8 screening visit (applies to all participants regardless of whether previous biopsy results are available at screening).

[0300] Participants had a biopsy-confirmed diagnosis of NASH (NAS score ≥ 4 with at least 1 point each in steatosis, ballooning, and lobular inflammation) and liver fibrosis stage F2, F3, or F4cc according to the NASH CRN, established according to appropriate guidelines.

[0301] Participants are male participants or non-pregnant, non-lactating female participants or female participants of no childbearing potential who, if sexually active, agree to comply with the protocol's contraceptive requirements. Sexually active participants of reproductive potential must agree to use adequate contraception (i.e., a highly effective method for female participants and a medically appropriate method for male participants) during the study and for at least 12 weeks after the final dose of study medication.

[0302] If participants are able to breastfeed, they will provide informed consent to abstain from breastfeeding for 12 weeks after the final administration of study medication.

[0303] Exclusion criteria Participants will be excluded if they meet any of the following exclusion criteria:

[0304] Condition: Participants will be excluded if any of the following laboratory findings are present at either the screening visit (weeks -8 or -6) or visit 4a2 (day -4): a.AST levels >5x the upper limit of normal (ULN). b. ALT level >5x ULN

[0305] Participants will be excluded if any of the following laboratory findings are present during screening (week -8 or week -6): ALP value is ≥2 times the ULN. b. Serum creatinine ≥ 1.5 times ULN or estimated glomerular filtration rate (eGFR) < 45 mL / min / 1.73 m2. c.INR ≥ 1.3 (excluding participants receiving anticoagulation therapy). d.TBL above ULN (if direct bilirubin is within normal reference range, excluding patients with a history of Gilbert syndrome). e. Direct bilirubin ≥3 times ULN. f. Platelet count is 60 x 10 9 / L or less.

[0306] Participants must have been diagnosed with decompensated liver disease or have new signs of decompensation, and / or have a clinically meaningful change in disease status (including but not limited to clinically significant changes in TBL, albumin, INR, creatinine, and / or AST and ALT) as judged by the investigator during the screening period, or have any of the following during the screening period: a. Presence or history of ascites, hepatic encephalopathy, or variceal bleeding. b. Present or history of Child-Pugh score >6 (Class B or C), except when due to therapeutic anticoagulation. c. Presence or history of MELD score >12.

[0307] Participants had other causes of liver disease diagnosed based on medical history and / or baseline assessment of clinical and / or histological test results, including viral conditions (e.g., chronic hepatitis B / hepatitis B virus surface antigen [HBsAg] positive or hepatitis B core antibody [HBcAb] positive; or chronic hepatitis C / hepatitis C virus antibody [HCVAb] positive and hepatitis C virus [HCV] RNA positive; or human immunodeficiency virus [HIV] antibody positive), alcohol conditions (for male participants, alcohol consumption of more than 4 units on any day or 14 units per week). or for female participants, >3 units of alcohol per day or >7 units per week (1 unit of alcohol is present in one 12 oz / 355 mL bottle of beer (approximately 5% alcohol), one 5 oz / 148 mL glass of wine (approximately 12% alcohol), and one 1.5 oz / 44 mL shot of 80 proof spirits (approximately 40% alcohol)); or autoimmune conditions, including but not limited to PSC, primary biliary cirrhosis, autoimmune hepatitis, drug-induced hepatotoxicity, and other rare liver diseases, including, but not limited to, alpha-1 antitrypsin deficiency, Wilson's disease, and hemochromatosis.

[0308] If a participant tests negative for HBsAg but positive for HBcAb, they will be considered eligible if the absence of hepatitis B virus (HBV) DNA is confirmed by a central laboratory-performed HBV DNA polymerase chain reaction (PCR) reflex test. Participants who are HCVAb-positive without evidence of HCV RNA may be considered eligible (either spontaneously resolved or previously treated and cured [defined as no evidence of HCV RNA at least 12 weeks prior to baseline]).

[0309] Participant has a history of a hemostatic disorder that, in the judgment of the investigator, would place the participant at increased risk if participating in the study. Participant has a significant concurrent medical condition at screening or baseline, including, but not limited to: a. Any major disease / condition or evidence of an unstable clinical condition (e.g., hepatic, renal, hematological, gastrointestinal (GI), endocrine (e.g., unstable diabetes or type 1 diabetes, or thyroid disease), neurological (pre-existing demyelinating disease such as multiple sclerosis or new-onset stroke, unexplained sensorimotor or cognitive-behavioral neuropathy, or significant abnormalities noted during screening), cardiovascular, pulmonary, immune (e.g., Felty's syndrome), disease, or local active infection / infectious disease (any bacterial, fungal, or viral, e.g., clinically active cytomegalovirus, Epstein-Barr virus, herpes simplex virus) that significantly increases the participant's risk Participants with a hemoglobin A1c (HbA1c) of 6.5% or greater at screening (week -8) without a previous diagnosis of T2DM should not be included in the study. Participants with a previous diagnosis of T2DM will be allowed to participate in the study if they have been on stable antidiabetic therapy for at least 90 days prior to screening. Participants who are on a stable regimen of antidiabetic therapy for at least 90 days prior to screening (week -8) and have an HbA1c of 8% or greater at screening (week -8) should be excluded. Participants with uncontrolled T2DM (i.e., HbA1c of 9% or greater) should be excluded. b. Presence of acute coronary syndrome (e.g., acute myocardial infarction, unstable angina) within 24 weeks prior to screening. c. History of significant cerebrovascular disease within 24 weeks prior to screening. d. Cancer or history of cancer, such as hepatocellular carcinoma or cholangiocarcinoma, or lymphoproliferative disorder within the past 5 years (excluding excised basal cell carcinoma of the skin, squamous cell carcinoma, or intraepithelial carcinoma of the cervix that has been treated and has no evidence of recurrence). e. Any other severe acute or chronic medical or psychiatric condition or clinical laboratory or electrocardiogram abnormality that may increase the risks associated with study participation or study drug administration or that may interfere with the interpretation of study results and that, in the judgment of the investigator, make the participant unsuitable for entry into the study. f. History of organ or liver transplantation. g. Major trauma or major surgery within 4 weeks prior to screening visit, or major elective surgery scheduled to occur during the study.

[0310] Participants must have severe, active inflammatory bowel disease (IBD). Participants with inactive IBD or mild-to-moderately active IBD, confirmed by prior endoscopy or documented in their medical records for more than 6 months, are eligible to participate if they do not require biologic therapy or a JAK inhibitor.

[0311] Participants have a severe immune-mediated inflammatory disease (IMID) (e.g., rheumatoid arthritis, spondylitis spectrum arthritis, connective tissue disorders, skin inflammatory conditions such as psoriasis, atopic dermatitis, hidradenitis suppurativa, asthma, multiple sclerosis). Participants with inactive IMID or active IMID of mild to moderate severity are eligible to participate in the study.

[0312] Participants must have a weight change of 5% or more in the 3 months prior to the start of screening or after the qualifying liver biopsy. If participants have had a liver biopsy within 6 months of screening but have experienced a weight change of 5% or more since the date of liver biopsy, they must have a repeat liver biopsy at screening.

[0313] Participants will have any laboratory abnormalities or conditions that, in the opinion of the investigator, may adversely affect the participant's safety or impair the assessment of study results.

[0314] Participants had a history of hypersensitivity to MAdCAM antibodies or formulation excipients.

[0315] Participants had active or latent Mycobacterium tuberculosis (TB) infection and had not completed a full course of commonly accepted treatment before screening.

[0316] Participants will have an abnormal chest radiograph, such as active TB, common infection, heart failure, or the presence of malignancy, at screening (Visit 1) or, if available, within a maximum of 12 weeks prior to the first screening.

[0317] Participants must have a positive interferon-gamma release assay (IGRA) at screening or within 12 weeks prior to screening despite the absence of previously diagnosed active or latent TB. IGRA screening may be repeated during the screening period if the initial result is indeterminate. Participants may be enrolled if the IGRA confirmation result from the central laboratory is negative. If the IGRA confirmation result from the central laboratory is positive, the participant should be screened out. If both the initial and confirmatory IGRA results are indeterminate, participants may be enrolled after a negative Mantoux tuberculin skin test and after consultation with the sponsor and a pulmonary or infectious disease specialist, who determines that the risk of infection is low (i.e., the participant is allowed immunosuppressive medication [e.g., anti-tumor necrosis factor (TNF)] without further action). If the consultation time exceeds the consultation period, the participant should be screened out and may be screened again after the consultation confirms eligibility for study participation. This consultation must be included in the participant's medical history.

[0318] Participants have any unexplained symptoms suggestive of PML based on a targeted neurological assessment during the screening period.

[0319] Participants have human immunodeficiency virus (HIV).

[0320] Participants have active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

[0321] Participants have medical conditions (eg, morbid obesity, claustrophobia) that prevent them from undergoing protocol procedures such as percutaneous liver biopsy, LSM with FibroScan, and MRI.

[0322] Prior and concomitant treatment: Participants must have been receiving treatment with vitamin E, a thiazolidinedione (TZD), or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) for 3 months on a stable dose before the qualifying liver biopsy, unless initiated after the qualifying liver biopsy, and are expected to maintain the same dosing regimen during study participation.

[0323] Participants were using medications, herbs, or supplements historically associated with the cause or exacerbation of NAFLD / NASH within 6 months prior to the qualifying liver biopsy or at any time after the qualifying liver biopsy (including the use of total parenteral nutrition).

[0324] Participants will have a positive urine screen for amphetamines, cocaine, or opioids at screening.

[0325] Participants must be receiving methadone or buprenorphine unless they have been on stable maintenance treatment for at least 6 months prior to screening. Participants with a positive urine drug screen due to prescription opioid medication will be eligible if the prescription and diagnosis are reviewed and approved by the study physician.

[0326] Participants had received a live (attenuated) vaccine within 4 weeks prior to baseline or were expected to receive a live vaccine during the study.

[0327] Excluded procedures and treatments: Participants were taking any of the prohibited concomitant medications listed below. Table 9 details the minimum required duration before baseline (Day 1) for common prior treatments that are excluded medications for this study.

[0328] [Table 9]

[0329] In Table 9, TNF stands for tumor necrosis factor. The minimum duration for investigational drugs is 30 days, or 5 half-lives if longer. The minimum required duration before baseline (Day 1) for non-biologics with immunomodulatory properties is 90 days, excluding participants taking a stable dose of a non-biologic with immunomodulatory properties (e.g., azathioprine, 6-mercaptopurine, or methotrexate).

[0330] Antiplatelet and anticoagulant medications should be temporarily discontinued before liver biopsy during the study, if it is safe to do so, as described below (Neuberger et al., "Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology", Gut, 69(8), 1382-403(2020)) or according to local guidelines, if more stringent: Clopidogrel, prasugrel, and ticagrelor: discontinue for 7 days before liver biopsy Aspirin: Discontinue for 3 to 7 days before liver biopsy Dual antiplatelet therapy (e.g., aspirin / clopidogrel): Discontinue clopidogrel as above but continue aspirin Dipyridamole: Omit on the day of liver biopsy Low-molecular-weight heparin: For prophylactic doses, discontinue 12 hours before liver biopsy; for higher doses, discontinue 24 hours before liver biopsy Direct oral anticoagulants: discontinue for 2 days before liver biopsy

[0331] Systemic antibiotics that may affect the composition of the gut flora (including, but not limited to, clindamycin, ciprofloxacin, amoxicillin / clavulanate, cefprozil, imipenem, colistin / amoxicillin, amoxicillin / clavulanate potassium, and tetracycline) are prohibited for more than 2 weeks within the 3 months prior to the first dose of study medication (and, if applicable, within the 3 months prior to and not initiated after the qualifying prior liver biopsy) and will be excluded during the study.

[0332] Participants must not have taken any of the following drugs from the list of prohibited substances within 6 months prior to the first dose of study treatment, which will be excluded during the study: tamoxifen, amiodarone, alcohol (described below), griseofulvin, total parenteral nutrition, obeticholic acid, valproic acid, nucleoside analogues (except acyclovir), estrogen used in hormone replacement therapy at doses greater than 2 mg once daily, anabolic steroids, any known hepatotoxins, over-the-counter medications and herbal remedies such as germander, chaparral, and ephedra (ma-huang).

[0333] Alcohol intake of more than 21 units / week for men and 14 units / week for women (1 unit / 30 mL of alcohol is present in one 12 oz / 360 mL bottle of beer, one 4 oz / 120 mL glass of wine, and one unit / 30 mL shot of 40% proof alcohol) was not permitted within 24 weeks prior to the first dose of study treatment.

[0334] This is not a comprehensive list. Therapeutic agents not listed above are generally considered acceptable unless they are considered to be potential liver toxins.

[0335] Previous / contemporary clinical trial experience Participants must have participated in another clinical trial of a drug or device within 1 month or 5 half-lives of the previous investigational drug (whichever is longer) prior to screening.

[0336] Participants had participated in another clinical trial targeting NASH, T2DM, or obesity within 6 months prior to screening.

[0337] Participants are simultaneously participating in another therapeutic clinical trial.

[0338] Participants had previously received a MAdCAM antibody.

[0339] Participants had been exposed to previous anti-integrin or anti-adhesion molecule treatment, e.g., natalizumab, efalizumab, etrolizumab, vedolizumab, or any other investigational anti-integrin / adhesion molecule, within 90 days prior to baseline.

[0340] Participants had been previously exposed to any other biologic with immunomodulatory properties, e.g., biosimilars or anti-tumor necrosis factor (anti-TNF) such as anti-IL-12 / 23, or any non-biologic treatment with immunomodulatory properties, such as JAK inhibitors, within 90 days or 5 half-lives (whichever is longer) prior to baseline.

[0341] Acceptable Concomitant Medications and Treatments Medications and supplements used to treat NAFLD / NASH, including but not limited to vitamin E, betaine, s-adenosyl-l-methionine, ursodeoxycholic acid, statins, milk thistle, fibrates (e.g., gemfibrozil), probiotics, biguanides (metformin), bile acid sequestrants (e.g., cholestyramine or colestipol), TZDs, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and GLP-1 RAs, are permitted during the study if participants are on a stable dosing regimen (i.e., the same dose and frequency as in the 3 months prior to the qualifying liver biopsy and have not been initiated after the qualifying liver biopsy) and are therefore expected to maintain this dosing regimen throughout study participation. The use of antiplatelet medications is also permitted. The investigator must communicate with the contract research organization (CRO) medical monitor to discuss any changes to concomitant medications that may affect the study.

[0342] Participants taking 5-aminosalicylates, glucocorticoids, or immunosuppressants (e.g., azathioprine, 6-mercaptopurine, or methotrexate) for IMID should have been on a stable dose for at least 12 weeks prior to screening and should be expected to remain stable throughout the study.

[0343] Example 4: Test Treatments and Combination Therapies Test treatment The study drug is a MAdCAM-1 antibody (i.e., a fully human immunoglobulin G2 kappa anti-human MAdCAM-1 monoclonal antibody) provided in a sterile aqueous buffer solution for subcutaneous (SC) administration in a glass prefilled syringe (PFS) with a fixed needle. Each PFS contains 1 mL of MAdCAM antibody solution for injection at a concentration of 75 mg / mL. The MAdCAM antibody solution is administered on Day 1 and Q4W thereafter for up to 24 weeks (final dose at Week 20). The MAdCAM-1 antibody is stored and maintained at a temperature ranging from 2°C to 8°C.

[0344] Administration of test drug Study treatment (i.e., MAdCAM-1 antibody) will be administered SC Q4W at times specified in the activity schedule, which includes the treatment period, follow-up period, and end of study (Table 8).

[0345] Study medication will be administered into the anterolateral side of the right or left thigh. Injection sites will be rotated. If there are clinical reasons why the medication cannot be administered into the thigh, the medication will be administered into the deltoid region or abdomen and appropriately documented. After the first administration of study medication, participants will be observed for at least 30 minutes.

[0346] Example 5: Efficacy evaluation All efficacy assessment time points are provided under the activity schedule in Table 8.

[0347] Liver stiffness measurement and liver fat content Liver stiffness, measured by elastography, is a marker of liver fibrosis. It is quantified by ultrasound-based transient elastography (FibroScan). Transient elastography correlates well with histology (Metavir and Ishak stages), performing best at the extreme stages, i.e., severe fibrosis versus no fibrosis. Furthermore, the rate of change over time correlates with clinical outcomes.

[0348] FibroScan assessments (LSM by FibroScan and liver fat content by CAP) will be performed at the time points specified in Table 8. Results will be read locally and the baseline readings at the initial screening visit will be used to calculate the FAST score and determine eligibility for liver biopsy.

[0349] FibroScan-Aspartate Aminotransferase Score The FAST score was developed to identify NASH patients with a high NAS score (NAS ≥ 4) and advanced fibrosis (F ≥ 2). The FAST score consists of liver stiffness measurement (LSM) by damped transient elastography and controlled attenuation parameter (CAP), both measured by FibroScan and AST. The FAST score provides an efficient method for noninvasively identifying patients at risk for advanced NASH for clinical trials, thereby reducing unnecessary liver biopsies.

[0350] A FAST score of 0.35 or greater at the first screening visit (week -8), along with a Pro-C3 level greater than 12.6 ng / mL and an ELF score of 7.7 or greater, determines eligibility for liver biopsy during screening. The FAST score is calculated using the following formula:

[0351]

number

[0352] To calculate the FAST score, LSM and CAP should be obtained from a single FibroScan. The FibroScan and blood draw for AST assessment should be performed within 6 months.

[0353] FAST scores are calculated using myFibroScan software. FAST scores are calculated at the time points specified in Table 8.

[0354] Agile4 Score The Agile4 score was developed as a noninvasive test to identify cirrhosis in patients with NAFLD. The Agile4 score is derived from FibroScan and includes LSM, AST, ALT, platelets, diabetes status, and gender. An Agile4 score of 0.57 or higher during screening is consistent with a high probability of F4 fibrosis (i.e., cirrhosis). Agile4 has been independently validated and has demonstrated superior positive predictive value for identifying patients with cirrhosis compared with FIB-4 or LSM alone. Agile4's rule-out and rule-in cutoffs are associated with much smaller uncertainty zones for ruling out or confirming cirrhosis compared with FIB-4 and LSM alone. Agile4 can be used in clinical practice to identify patients who require screening for hepatocellular carcinoma and esophageal varices.

[0355] The Agile4 score is calculated at the times specified in Table 8.

[0356] Fibrosis-4 Index The FIB-4 index is a non-invasive test for liver fibrosis. The FIB-4 score is composed of age, ALT, AST, and platelet count, and is calculated using the following formula: age [years] × AST [U / L] / (platelet count [10 9 / L]×√ALT[U / L]).

[0357] The FIB-4 has utility in identifying participants with advanced liver fibrosis and in prognosticating mortality and liver-related outcomes. An FIB-4 score of 3.48 or greater and an LSM of 20 kPa or greater at screening indicate a high likelihood of F4 fibrosis (i.e., cirrhosis). The FIB-4 score is calculated at the time points specified in Table 8.

[0358] Child-Pugh score The Child-Pugh score is a scoring system for measuring the severity of chronic liver disease, including cirrhosis. It consists of five clinical features, three of which assess liver synthetic function (TBL level, serum albumin, and INR) and two of which are based on clinical assessment (degree of ascites and degree of hepatic encephalopathy). The Child-Pugh score is calculated at the time points specified in Table 8.

[0359] End-stage liver disease model The original Model for End-Stage Liver Disease (MELD) score is a prospectively developed and validated chronic liver disease severity scoring system that predicts 3-month survival using patient laboratory values ​​for serum bilirubin, serum creatinine, and prothrombin time (INR). In patients with cirrhosis, increasing MELD scores are associated with increased severity of liver dysfunction and increased 3-month mortality risk.

[0360] The MELD score changes over time depending on the course of chronic liver disease, ranging from 6 to 40, with increasing scores indicating disease progression / worsening. The MELD score is calculated at the time points specified in Table 8.

[0361] Liver biopsy A reasonable attempt should be made to obtain a liver core needle biopsy specimen using a 16-gauge needle at least 2.0 cm long (expected to obtain 11 or more portal vein segments). Specimens smaller than 1.5 cm will not be accepted for evaluation. A second core sample should be taken if the first sample is not at least 1.5 cm long. The anatomical location (right or left liver lobe) and specimen adequacy (needle size, tissue length) should be recorded. All biopsy tissue obtained should be submitted for central pathology review.

[0362] Liver biopsy specimens are processed into formalin-fixed, paraffin-embedded blocks and routinely stained with hematoxylin and eosin (H&E) and Masson's trichrome (MTR) in a central laboratory. Stained slides are used to confirm the diagnosis of NASH, assess and grade NAS activity (steatosis, lobular inflammation, and ballooning), and score fibrosis by a hepatic pathologist using the NASH CRN scoring system. The NASH CRN score and its components (i.e., lobular inflammation, hepatocyte ballooning, and steatosis grade) and NAS are used to compare pre- and post-treatment outcomes.

[0363] A previous biopsy performed as part of standard of care that meets the above criteria for an adequate liver biopsy, but no earlier than 1 month and no later than 6 months prior to the start of the screening period (or within 3 months of the start of the screening period for any F4 participant who met the inclusion and exclusion criteria before safety and tolerability were established in the first four F2 / F3 participants), may be substituted for a fresh biopsy, provided that a sufficient number of sections (stained or unstained) and uncut biopsy blocks are made available to the sponsor as outlined in the Histopathology Manual. If the previous biopsy is found to be insufficient by the study pathologist, a fresh biopsy will be required. The week 24 liver biopsy should be taken from the same lobe as the screening biopsy.

[0364] Residual tissue samples may be archived and stored for RNA sequencing (transcriptomics) analysis or other potential further analyses. Any archived samples will be anonymized and will not be labeled with patient-identifying information. Fifteen years after the end of the study, or sooner if required by local regulations, samples may be returned to the sponsor's repository or disposed of in accordance with local regulations. Furthermore, with participant consent, samples may be used for further research by the sponsor or others, such as universities or other companies, to contribute to the understanding of NASH or other diseases, the development of related or new treatments, or the development of research methods.

[0365] Multiparametric magnetic resonance imaging: iron-corrected T1 The LiverMultiScan® MRI is a fast, contrast-free MRI scan that provides a quantitative assessment of whole liver tissue by measuring fibrosis as well as biomarkers of inflammation, fat, and iron. As part of the LiverMultiScan® technology, the owner company segments whole slices of liver parenchyma and quantifies iron-corrected T1 (cT1) relaxation time values ​​across the liver tissue slice to capture disease heterogeneity in the analysis. cT1 measurements have been shown to correlate with histopathological features of NASH. Abdominal MRI (for liver cT1 acquisition) will be performed at the time points specified in Table 8.

[0366] HepQuant Shunt Disease Severity Index The Cholic Acid Duplex Test (HepQuant®-SHUNT) is an exploratory assay. 13 The DSI quantifies overall liver function and physiology by measuring hepatic filtration volume, defined as the clearance of C (20 mg intravenously, "systemic") and cholic acid-2,2,4,4-d4 (40 mg orally; "portal target"). The HepQuant-SHUNT DSI quantifies liver injury and is reproducible across a wide range of etiologies, fibrosis stages, and clinical severity of liver disease. The HepQuant-SHUNT DSI is optional if the site is unable to perform this assessment, but is not optional for participants if the site is able to perform this assessment. The HepQuant-SHUNT DSI will be performed at the time points specified in Table 8.

[0367] Alcohol screening The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item screening tool developed by the World Health Organization (WHO) to assess alcohol use, drinking behaviors, and alcohol-related problems (nida.nih.gov / sites / default / files / audit.pdf). Both clinician-administered and self-report versions of the AUDIT are included in this assessment. Participants are asked to answer questions on the AUDIT regarding their typical drinking habits. A score of 8 or higher is considered to indicate hazardous or harmful alcohol use. The AUDIT has been validated across a wide range of racial / ethnic groups and genders and is suitable for use in primary care settings.

[0368] The audit will be conducted at the times specified in Table 8.

[0369] Additional biomarkers C-reactive protein and calprotectin are important biomarkers of inflammation. There is a significant relationship between hsCRP and the risk of disease progression in NAFLD and NASH. Yoneda et al., "High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH," J Gastroenterol, 42(7), 573-82 (2007). Pro-C3 is an important biomarker of liver fibrosis. Mixed-action antimetabolites (FGF19 / 21 analogs) that affect inflammatory pathways (e.g., NF-kB) reduce Pro-C3 by at least 20% during short-term studies of 16 weeks or less, which is considered a clinically important change (i.e., improvement in liver fibrosis by one or more stages in longitudinal studies). Luo et al., "An evaluation of the collagen fragments related to fibrogenesis and fibrolysis in nonalcoholic steatohepatitis", Sci Rep, 8(1), 12414 (2018). In an open-label, 12-week phase 2a study using aldafermin, Pro-C3 and ELF levels were significantly reduced in patients with histological responses compared to histological non-responders (histological response was defined as an improvement of ≥2 points on the NAS without worsening fibrosis, or an improvement of ≥1 stage of fibrosis without worsening NASH [defined as no increase in the NAS for ballooning, inflammation, or steatosis]).Harrison et al., "Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis," Gastroenterology, 160(1), 219-31.e1 (2021). Liver disease biomarkers, such as ELF, are derived as a composite score from serum concentrations of TIMP-1, PIIINP, and HA. ELF is the first prognostic tool approved by the FDA for patients with advanced fibrosis (F3 or F4) due to NASH. Elevated ELF levels are prognostic for progression to cirrhosis (ELF ≥ 9.8) and liver-related clinical events (ELF ≥ 11.3) in patients with advanced fibrosis due to NASH. Fagan et al., “ELF score ≥ 9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis, and histological activity”, Liver Int, 35(6), 1673-81 (2015); Harrison et al., “Prospective validation of the enhanced liver fibrosis (ELF) test for the prediction of disease progression in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis”, Abstract No. 2122. Hepatology, 66, 1120A-1A (2017). Magnetic resonance imaging-proton density fat fraction (MRI-PDFF), part of Liver MultiScan®, has excellent correlation with histological steatosis across the NAFLD spectrum and has high diagnostic accuracy in stratifying all grades of fatty liver (Dennis et al. 2021).Splenic cT1 correlates significantly with hepatic venous pressure gradient (HVPG) and has excellent diagnostic accuracy for portal hypertension (HVPG >5mmHg) and clinically significant portal hypertension (HVPG >10mmHg), with an area under the receiver operating characteristic curve of 0.92 for both. Levick et al., "Non-invasive assessment of portal hypertension by multi-parametric magnetic resonance imaging of the spleen: A proof of concept study," PLoS One, 14(8), e0221066 (2019).

[0370] Blood samples and liver biopsy specimens will be collected at the time points specified in Table 8. ●Serum Pro-C3 Serum ELF and its components (TIMP-1, PIIINP, and HA) ●Serum soluble MAdCAM-1 Serum and plasma markers of inflammation, fibrosis, and trafficking, including but not limited to hsCRP, calprotectin (plasma), IL-8, CTXIII, C3M, TSP2, and Pro-C5 Exploratory analysis of liver biopsies, including but not limited to markers of inflammation and fibrosis, and artificial intelligence / machine learning methods Th17 / Th1 vs. Th2, β7 + Trafficking of T cells and immune cells in liver biopsy specimens (immunohistochemistry) and circulating whole blood samples, including T cells, CCR9, and CXCR3 Transcriptomics using remnant liver biopsy and whole blood samples

[0371] Blood samples should be taken before administration of the study drug. The ELF score is calculated from the concentrations of serum biomarkers, namely TIMP-1, PIIINP, and HA.

[0372] Samples may be stored for up to 15 years after the end of the study to achieve the study objectives. Furthermore, with participant consent, samples may be used for further research by the study sponsor or others, such as universities or other companies, to contribute to the understanding of NASH or other diseases, the development of related or new treatments, or the development of research methods.

[0373] Example 6: Safety evaluation All safety evaluation time points are provided under the activity schedule in Table 8.

[0374] Targeted neurological assessment Targeted neurological evaluations to monitor for the development of signs and / or symptoms of progressive multifocal leukoencephalopathy (PML) will be conducted at the time points specified in Table 8. Participants will be evaluated to uncover any potential abnormalities in the following neurological domains: vision, motor, tactile, coordination / cerebellar function, speech, language comprehension, and cognitive / behavioral domains. If abnormalities are noted, the participant will be further evaluated to help clarify the underlying abnormal response, with a focus on possible alternative etiologies (e.g., fracture or stroke). If additional evaluation reveals new abnormalities of unknown etiology, neurological examination(s) targeted to the abnormal domain will be performed by the study investigator or qualified personnel.

[0375] Hypersensitivity Monitoring Participants will be monitored at the time points specified in Table 8 for the presence of Type I (anaphylaxis) and Type III (immune complex) hypersensitivity reactions (e.g., fever, skin rash including hives, arthralgia, myalgia, vasculitis, Arthus reaction, general discomfort, itching, and lymphadenopathy).

[0376] Participants experiencing an adverse event (AE) suggestive of a type I hypersensitivity reaction will have a blood sample (3 mL) collected for determination of anti-MAdCAM-1 immunoglobulin E antibodies. Participants with a suspected type III hypersensitivity reaction will have a blood sample (4 mL) collected for complement determination (C3a, C5b-9).

[0377] Pharmacokinetics Blood samples for measuring serum MAdCAM-1 antibody concentrations will be collected at the time points specified in Table 8. Blood samples will be collected prior to study drug administration. Details of sample collection, handling, shipping, and bioanalysis are provided in the laboratory manual.

[0378] Immunogenicity assessment Blood samples for measurement of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) will be collected at the time points specified in Table 8. Blood samples will be collected at the visit prior to study drug administration. Detection and characterization of ADA and NAb will be performed using validated assay methods.

[0379] Example 7: Endpoints relevant to each objective Each of the study's endpoints is shown against each objective in Table 10.

[0380] [Table 10-1]

[0381] [Table 10-2]

[0382] [Table 10-3]

[0383] [Table 10-4]

[0384] [Table 10-5]

[0385] Example 8: Second Study Design and Methods The second study is a multiple-dose, placebo-controlled trial. Briefly, the study included subjects with a CRN fibrosis score of 2 or 3, an NAS score of 4 or greater, and at least 1 point each in inflammation and ballooning.

[0386] The trials will include MAdCAM-1 antibody at doses ranging from 25 mg, 75 mg, or 150 mg, or placebo, randomized in a 1:1:1:1 or 2:1:2:2 ratio. Treatment duration will range from 52 to 72 weeks.

[0387] The primary endpoint of the study required improvement of fibrosis (≥1 stage) without worsening of NASH, and / or resolution of NASH without worsening fibrosis (NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis).

[0388] Some key secondary endpoints include inflammatory markers, liver biochemistry, MRI-cT1, Fibroscan, PK, PROs, HRQoL, and healthcare utilization.

[0389] Example 9: Design and methods of the third study The third test is a histological study that includes subjects with a CRN fibrosis score of 2 or 3, an NAS score of 4 or greater, and at least 1 point each for inflammation and ballooning.

[0390] The study will include selected doses from the second study versus placebo or standard of care. The treatment period will last up to 104 weeks.

[0391] The primary endpoint of the study required improvement of fibrosis (≥1 stage) without worsening of NASH, and / or resolution of NASH without worsening fibrosis (NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis).

[0392] Several key secondary endpoints include improvement in fibrosis (≥1 stage) without progression of NASH, as well as inflammatory markers, liver biochemistry, MRI-cT1, Fibroscan, PK, PROs, HRQoL, and healthcare utilization.

[0393] Example 10: Fourth Biomarker Study Design and Methods The fourth study is a biomarker study that includes NASH subjects based on elevated non-invasive markers and biomarkers.

[0394] The study will include selected doses from the second study. The treatment period will last 52 weeks.

[0395] The primary endpoint of the study will involve markers of fibrosis and inflammation.

[0396] Some important secondary endpoints include liver biochemistry and metabolic parameters.

[0397] Example 11: Fifth Study Design and Methods The fifth study was a post-approval outcome study and included subjects with a CRN fibrosis score of 2 or 3, an NAS score of 4 or greater, and at least 1 point each in inflammation and ballooning. Patients rolled over from the Phase 3 histology study.

[0398] The study will include selected doses from the second study versus placebo or standard of care. Treatment duration will range from 3 to 5 years.

[0399] The primary endpoints of the study included progression of cirrhosis on histopathology, reduction in decompensated cirrhosis events, change in MELD score from 12 or less to 15 or more, liver transplantation, and all-cause mortality.

[0400] Some key secondary endpoints include inflammatory markers, liver biochemistry, MRI-cT1, Fibroscan, PK, PROs, HRQoL, and healthcare utilization.

[0401] Example 12: Sixth Study Design and Methods The sixth study is a long-term safety study that will include subjects from the second, third, fourth, and / or fifth rollovers. The study will include selected doses from the second study. The treatment period will continue until marketing approval.

[0402] The primary endpoints of the study include safety (AEs, SAEs, etc.) and product-specific safety evaluation items.

[0403] Some important secondary endpoints include inflammatory markers, liver biochemistry, MRI-cT1, and medical utilization.

[0404] Equivalents and Scope Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Detailed Description, but rather is as set forth in the following claims.

Claims

1. 1. A method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis, comprising administering to said patient a therapeutic amount of 20 mg to 125 mg of a MAdCAM-1 antibody.

2. The method of claim 1, further comprising administering a subsequent dose of a MAdCAM-1 antibody.

3. Either or both of the therapeutic amount and the subsequent doses of the MAdCAM-1 antibody have a lower limit of 1 mg, 2 mg, 2.25 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg and an upper limit of 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 3. The method of claim 1 or 2, wherein the medicament is administered in a range that is 1 mg, 60 mg, 65 mg, 70 mg, less than 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.

4. The method of claim 1 or 3, comprising administering to the patient a therapeutic amount of 22.5 mg or 75 mg of a MAdCAM-1 antibody.

5. 5. The method of claim 1, 3, or 4, comprising administering to said patient a therapeutic amount of 75 mg of MAdCAM-1 antibody.

6. The method of claims 1 to 5, wherein the MAdCAM-1 antibody comprises a light chain CDR1 of SEQ ID NO: 11, a light chain CDR2 of SEQ ID NO: 12, and a light chain CDR3 of SEQ ID NO: 13, and a heavy chain CDR1 of SEQ ID NO: 14, a heavy chain CDR2 of SEQ ID NO: 15, and a heavy chain CDR3 of SEQ ID NO:

16.

7. The method of any one of claims 1 to 6, wherein the MAdCAM-1 antibody comprises a variable light chain of SEQ ID NO:3 and a variable heavy chain of SEQ ID NO:

4.

8. The method of any one of claims 1 to 7, wherein the MAdCAM-1 antibody comprises SEQ ID NO: 1 for the light chain and SEQ ID NO: 2 for the heavy chain.

9. 6. The method of any of claims 1-5, wherein the subsequent dose is administered in an amount that is the same as or less than the therapeutic dose, and wherein the subsequent dose is administered between about 1 week and about 12 weeks after the therapeutic dose.

10. 10. The method of claim 2, 3, or 9, wherein the subsequent doses are administered every four weeks.

11. 10. The method of claim 2, 3, or 9, wherein the subsequent doses are administered every 8 weeks.

12. The method of any one of claims 1 to 11, wherein the MAdCAM-1 antibody is administered subcutaneously to the patient.

13. The method of any one of claims 1 to 11, wherein the MAdCAM-1 antibody is administered to the patient intravenously.

14. The method of any one of claims 1 to 13, wherein the patient is not taking a TNF antagonist or TNF inhibitor.

15. A MAdCAM-1 antibody for use in the method according to any one of claims 1 to 14.

16. A pharmaceutical composition comprising the MAdCAM-1 antibody of claim 15.

17. Use of the MAdCAM-1 antibody of claim 15 in the manufacture of a medicament for the treatment of nonalcoholic steatohepatitis.

18. A method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis, comprising administering to the patient a therapeutic amount of 22.5 mg or 75 mg of a MAdCAM-1 antibody comprising a light chain CDR1 of SEQ ID NO: 11, a light chain CDR2 of SEQ ID NO: 12, and a light chain CDR3 of SEQ ID NO: 13, and a heavy chain CDR1 of SEQ ID NO: 14, a heavy chain CDR2 of SEQ ID NO: 15, and a heavy chain CDR3 of SEQ ID NO:

16.

19. 19. The method of claim 18, comprising administering to said patient a therapeutic amount of 75 mg of MAdCAM-1 antibody.

20. The method of claim 18 or 19, wherein the MAdCAM-1 antibody comprises a variable light chain of SEQ ID NO:3 and a variable heavy chain of SEQ ID NO:

4.

21. The method of claim 18 or 19, wherein the MAdCAM-1 antibody comprises SEQ ID NO: 1 for the light chain and SEQ ID NO: 2 for the heavy chain.

22. 20. The method of claim 18 or 19, further comprising administering a subsequent dose, wherein said subsequent dose is administered in an amount that is the same as or less than said therapeutic dose, and wherein said subsequent dose is administered between about 1 week and about 12 weeks after said therapeutic dose.

23. 23. The method of claim 22, wherein the subsequent doses are administered every four weeks.

24. The method of any one of claims 18 to 23, wherein the MAdCAM-1 antibody is administered to the patient subcutaneously or intravenously.

25. 26. A method for assessing the presence or absence of a beneficial response in a patient with non-alcoholic steatohepatitis at different stages of fibrosis after subcutaneous administration of a MAdCAM-1 antibody of any one of claims 1 to 25 at a dose of 22.5 mg or 75 mg to said patient, comprising: (a) measuring the level of biomarkers in a biological sample from the patient, wherein the biomarkers are (i) neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3), and (ii) enhanced liver fibrosis (ELF); (b) comparing the level with a control; The method, wherein an alteration in the level of the biomarker compared to the control is predictive of a beneficial response in the patient.

26. 1. A method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis, comprising administering to said patient a therapeutic amount of 25 mg to 150 mg of a MAdCAM-1 antibody.

27. The method of claim 1, further comprising administering a subsequent dose of a MAdCAM-1 antibody.

28. Either or both of the therapeutic amount and the subsequent doses of the MAdCAM-1 antibody have a lower limit of 1 mg, 2 mg, 2.25 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 45 mg, 50 mg, 55 mg, 65 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg and an upper limit of 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg , 60 mg, 65 mg, 70 mg, less than 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.

29. 29. The method of claim 26 or 28, comprising administering to the patient a therapeutic amount of 25 mg, 75 mg, or 150 mg of MAdCAM-1 antibody.

30. 30. The method of claim 26, 28, or 29, comprising administering to the patient a therapeutic amount of 25 mg of a MAdCAM-1 antibody.

31. 30. The method of claim 26, 28, or 29, comprising administering to the patient a therapeutic amount of 75 mg of MAdCAM-1 antibody.

32. 30. The method of claim 26, 28, or 29, comprising administering to the patient a therapeutic amount of 150 mg of a MAdCAM-1 antibody.

33. 33. The method of any of claims 26-32, wherein the subsequent dose is administered in an amount that is the same as or less than the therapeutic dose, and wherein the subsequent dose is administered between about 1 week and about 12 weeks after the therapeutic dose.

34. 33. The method of any of claims 26-32, wherein the subsequent dose is administered between about 1 week and about 24 weeks after the therapeutic dose.

35. 33. The method of any of claims 26-32, wherein the subsequent dose is administered between about 1 week and about 52 weeks after the therapeutic dose.

36. 33. The method of any of claims 26-32, wherein the subsequent dose is administered between about 1 week and about 72 weeks after the therapeutic dose.

37. 33. The method of any of claims 26-32, wherein the subsequent dose is administered between about 1 week and about 104 weeks after the therapeutic dose.

38. A method for treating a patient susceptible to or diagnosed with non-alcoholic steatohepatitis, comprising administering to the patient a therapeutic amount of 25 mg, 75 mg, or 150 mg of a MAdCAM-1 antibody comprising a light chain CDR1 of SEQ ID NO: 11, a light chain CDR2 of SEQ ID NO: 12, and a light chain CDR3 of SEQ ID NO: 13, and a heavy chain CDR1 of SEQ ID NO: 14, a heavy chain CDR2 of SEQ ID NO: 15, and a heavy chain CDR3 of SEQ ID NO:

16.

39. 39. The method of claim 38, comprising administering to the patient a therapeutic amount of 25 mg of MAdCAM-1 antibody.

40. 39. The method of claim 38, comprising administering to the patient a therapeutic amount of 75 mg of MAdCAM-1 antibody.

41. 39. The method of claim 38, comprising administering to said patient a therapeutic amount of 150 mg of MAdCAM-1 antibody.

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