RU2838150C1 - Treating liver disease or disorder involving use of actrii receptor antagonists - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: disclosed is the use of an activin receptor type II antibody (ActRII) or an antigen-binding fragment thereof for treating a liver disease or disorder in a subject in need thereof, where the liver disease or disorder is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hepatic fibrosis, as well as the use of an activin receptor type II antibody (ActRII) or an antigen-binding fragment thereof for the manufacture of a medicament for treating a liver disease or disorder in a subject.

EFFECT: invention can be used to treat a liver disease in a subject, where the disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hepatic fibrosis.

40 cl, 1 tbl, 10 dwg, 3 ex

Description

List of sequences

This application contains a sequence listing that was filed electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on July 14, 2020 is named PAT058683-WO-PCT_SL.txt and is 10,864 bytes in size.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[1] The present invention relates to activin type II receptor (ActRII) antagonists, e.g., molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs), and/or myostatin to the human ActRII receptor, e.g., an antagonist antibody to ActRIIA and/or ActRIIB, e.g., an antibody to the ActRII receptor, e.g., bimagrumab, for use in methods of preventing or treating a liver disease or disorder. The present invention also relates to methods of preventing or treating a liver disease or disorder by administering to a subject in need thereof a therapeutically effective amount of an antagonist of the ActRII receptor.

[2] The present invention also relates to a pharmaceutical combination comprising a) an activin type II receptor (ActRII) antagonist, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the human ActRII receptor, such as an ActRIIA and/or ActRIIB antagonist, such as an antibody to the ActRII receptor, such as bimagrumab, and b) at least one additional therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier, and to pharmaceutical compositions comprising them. The present invention is further directed to the use of such pharmaceutical combinations for the treatment or prevention of liver diseases or disorders, as well as compositions, methods, uses and regimens comprising such combinations.

BACKGROUND OF THE INVENTION

[3] Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the Western world (Ratziu et al. J Hepatol. 2010 Aug; 53(2):372-84). The main stages of NAFLD are: 1 - simple fatty liver (hepatic steatosis), in which excess fat accumulates in the liver cells through a process called steatosis (i.e., abnormal retention of lipids inside the cell); 2 - non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD in which hepatic steatosis progresses to progressive inflammation of the liver (hepatitis) called steatohepatitis; 3 - fibrosis, in which the liver experiences persistent inflammation, resulting in the formation of fibrous scar tissue around the liver cells and blood vessels; and 4 - cirrhosis, in which this damage is permanent and can lead to liver failure and liver cancer (hepatocellular carcinoma; HCC). Liver transplantation is the only treatment for progressive cirrhosis with liver failure, and transplantation is increasingly being performed in people with NASH.

[4] Steatosis, lobular inflammation, and hepatic cell ballooning are all components required for the diagnosis of NASH, and fibrosis is also commonly seen. The NAFLD activity score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. The score is calculated as the unweighted sum of the scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2).

[5] Estimates of the worldwide prevalence of NAFLD range from 6.3% to 33%, with a median of 20% in the general population. The estimated prevalence of NASH is lower, ranging from 3 to 5% (Younossi et al ., Hepatology, Vol. 64, No. 1, 2016). NASH is a global problem with an increasing prevalence over the past few decades. NASH is closely associated with metabolic syndrome and type 2 diabetes mellitus.

[6] Furthermore, cardiovascular mortality is an important cause of death in patients with NASH.

[7] Activin type 2 receptors (ActRIIA and ActRIIB, collectively abbreviated as ActRII) modulate signaling of ligands belonging to the transforming growth factor beta (TGF-β) superfamily, such as myostatin, GDF-11, and activins. Myostatin, activin A, and GDF-11 are negative regulators of skeletal muscle growth, acting through the ActRII receptor pathway to suppress muscle protein synthesis and myocyte differentiation and proliferation.

Bimagrumab (INN 9711, also known as BYM338 or MOR08159), a recombinant human monoclonal antibody, competitively binds ActRII with greater affinity than its natural ligands myostatin or activin. Bimagrumab is disclosed in WO 2010/125003, which is incorporated herein by reference. The sequences of bimagrumab disclosed in WO 2010/125003 are listed in Table 1. Bimagrumab demonstrated significant increases in skeletal muscle mass in healthy volunteers, in patients with sporadic inclusion body myositis (sIBM), and in patients with sarcopenia. In previous studies, a single dose of bimagrumab increased thigh muscle volume measured by magnetic resonance imaging by approximately 6% after 10 weeks in healthy lean adults compared with placebo and produced a comparable reduction in fat mass (Roubenoff and Papanicolaou, New treatments for muscle wasting: an update on bimagrumab and other treatments. Abstract at ICFSR 2015). A single dose of bimagrumab had a robust effect on body composition, with a maximal reduction in fat mass of ~8% and an increase in fat-free mass of ~3% (DXA) in overweight/obese prediabetic subjects (Garito et al, Diabetes Obes Metab. 2018 Jan; 20(1):94-102).

[8] There are currently no approved drugs to prevent or treat NAFLD, including NASH. Thus, treatment of liver-related diseases or disorders, particularly liver diseases such as NAFLD or NASH, represents a significant unmet medical need.

ESSENCE OF THE INVENTION

[9] The present invention relates in part to the discovery that directly inhibiting the binding of myostatin or activin to their ActRII receptors (preferably ActRIIB and ActRIIA or ActRIIA alone or ActRIIB) by administering ActRII-binding antibodies provides a significant reduction in liver fat content.

[10] Accordingly, the present invention is directed to activin type II receptor (ActRII) antagonists, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the human ActRII receptor, preferably an ActRIIA and/or ActRIIB antagonist, preferably an ActRIIA and/or ActRIIB antagonist antibody, most preferably bimagrumab, for use in the prevention or treatment of a liver disease or disorder. The present invention is also directed to methods for preventing or treating a liver disease or disorder by administering to a subject in need thereof a therapeutically effective amount of activin type II receptor (ActRII) antagonists, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the ActRII receptor, preferably an antagonist antibody to ActRIIA and/or ActRIIB, most preferably bimagrumab.

[11] As a potent ActRII inhibitor, bimagrumab blocks the effects of myostatin, activin A, GDF11, and possibly other ligands that act through these receptors (Lach-Trifilieff et al., Mol Cell Biol. 2014 Feb; 34(4):606-18).

[12] Thus, the present invention provides an activin type II receptor antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and more preferably an ActRII receptor antibody, most preferably bimagrumab, for use in reducing liver fat.

[13] Thus, the present invention provides an activin type II receptor antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and more preferably an ActRII receptor antibody, most preferably bimagrumab, for use in the treatment or prevention of a liver disease or disorder.

[14] In a similar aspect, the present invention provides an activin type II receptor antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and even more preferably an ActRII receptor antibody, most preferably bimagrumab, for use in the treatment or prevention of a liver disease or disorder in a patient, resulting in a reduction in liver fat content.

[15] In a similar aspect, the present invention provides an activin type II receptor, preferably an ActRIIA and/or ActRIIB antagonist, preferably an ActRII receptor antibody, most preferably bimagrumab, for use in the treatment, prevention or reduction of comorbidities associated with a liver disease or disorder, in particular those associated with increased liver fat mass.

[16] The present invention further provides a specific dosage regimen for the myostatin receptor antagonist bimagrumab for use herein.

[17] The present invention also relates to pharmaceutical combinations comprising a) an antagonist of the activin type II receptor (ActRII), such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the human ActRII receptor, preferably an antagonist of ActRIIA and/or ActRIIB, and more preferably an antibody to the ActRII receptor, most preferably bimagrumab, and b) at least one additional therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier, for use in the treatment or prevention of a liver disease or disorder, and pharmaceutical compositions containing them.

[18] Additional features and advantages of the present invention will become apparent from the following detailed description of the present invention.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Figure 1A-D: Shows body weight (Figure 1A), lean mass (Figure 1B), total fat mass (Figure 1C), and liver fat % (Figure 1D) in normal diet (ND)-fed mice (Group 3) and NASH diet-induced mice (HF/NASH) treated (+CDD866) (Group 1) and untreated (+control (ctrl) (Group 2) with CDD866 for 20 weeks.

Figure 2A-C: Picrosirius red (PSR) staining of liver sections at week 20 is shown for normal diet (ND) and HF/NASH-fed mice treated with (+CDD866) and not treated with (+control (ct)) CDD866 (murinized BYM338. Panel A) shows the PSR-stained area in ^mm2 , panel B) shows a representative image of PSR-stained liver sections, and panel C) shows the histopathological score.

Figure 2D-E: Shows immunohistological analysis of inflammation (IBA1) and fibrosis (anti-smooth muscle antibodies (aSMA) for normal diet (ND)-fed and NASH-fed mice treated with or without CDD866. Panel D shows the total area of aSMA-stained tissue and a representative image of aSMA-stained liver sections. Panel E shows the total number of IBA1-positive crown-like structures in the liver.

Figure 2F. Micro- and macrovesicular steatosis present in hematoxylin and eosin (H&E)-stained liver sections. Histopathological score and representative H&E-stained image are shown.

Figure 3A-D: Gene expression and serum analysis are shown in normal diet (ND)-fed and NASH-fed mice with or without CDD866 treatment. Panel A) shows gene expression levels of fibrosis markers, panel B) shows gene expression levels of inflammation markers, panel C) shows serum TIMP1 levels, and panel D) shows serum PIIINP levels.

Figure 4. Aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) levels are shown in normal diet (ND)-fed and NASH-fed mice treated with or without CDD866.

Figure 5A-E: Shows body weight (Figure 5A), lean mass (Figure 5B), total fat mass (Figure 5C), white adipose tissue (WAT) weight (Figure 5D), and brown adipose tissue (BAT) weight (Figure 5E) in control mice (Group 3) and CCl4-induced liver fibrosis mice treated with (+CDD866) (Group 1) and not treated with (+vehicle) (Group 2) for 28 days.

Figure 6A-B: Picrosirius red (PSR) staining of liver sections at week 4 is shown for control mice and for mice with CCl4-induced liver fibrosis treated (+CDD866) and untreated (+vehicle). Panel A) shows the area stained with PSR in mm ² , panel B) shows a representative image of liver sections stained with PSR.

Figure 6C-D: Shows immunohistological analysis of fibrosis (anti-smooth muscle antibodies (aSMA) at week 4 for control mice and for mice with CCl4-induced liver fibrosis treated (+CDD866) and not treated (+vehicle). Panel C) shows the total tissue area stained with aSMA, panel D) shows a representative image of liver sections stained with aSMA.

Figure 6E: Shows serum analysis of TIMP-1 and PIIINP levels in control mice and mice with CCl4-induced liver fibrosis treated (+CDD866) and untreated (+vehicle) at week 4.

Figure 7. Gene expression levels of fibrosis markers in control mice and mice with CCl4-induced liver fibrosis treated (+CDD866) and not treated (+vehicle) at week 4 are shown.

Figure 8. Shows total body fat mass values assessed by DXA in subjects receiving 10 mg/kg BYM338 or placebo from baseline to end of study (EOS) at week 56.

Figure 9A-B.Anthropometric characteristics are presented subjects receiving 10 mg/kg BYM338 or placebo from baseline to end of study (EOS) at week 56. Panel A) presents body weight in kg, Panel B) presents BMI (kg/m²).

Figure 10. Liver fat fraction values expressed as % are presented for subjects receiving 10 mg/kg BYM338 or placebo at baseline, week 24, and week 48.

DETAILED DESCRIPTION OF THE INVENTION

[19] The present invention relates to methods of treating or preventing a liver disease or disorder by administering to a subject in need thereof an effective amount of activin type II receptor (ActRII) antagonists, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the ActRII receptor, preferably an antagonist antibody to ActRIIA and/or ActRIIB, most preferably bimagrumab. Accordingly, in one aspect, there is provided a method of preventing or treating a liver disease or disorder comprising administering to a subject in need thereof an effective amount of bimagrumab. Also provided are activin type II receptor (ActRII) antagonists, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDF), bone morphogenetic proteins (BMPs) and/or myostatin to the human ActRII receptor, preferably an ActRIIA and/or ActRIIB antagonist antibody, most preferably bimagrumab, for use in the prevention or treatment of a liver disease or disorder. In one embodiment of any method or use of the present invention, said activin type II receptor (ActRII) antagonists provided therefor are an ActRIIA-binding and/or ActRIIB-binding antibody. In some embodiments of any and/or all of the methods or uses described herein, the ActRIIA-binding and/or ActRIIB-binding antibody is a neutralizing antibody.

Definitions

[20] In order to make the present invention easier to understand, some terms are first defined. Further definitions are provided in the detailed description.

[21] All patents, published patent applications, publications, references and other materials mentioned in this document are hereby incorporated by reference in their entirety.

[22] As used herein, the term “comprising” also includes “including” and “consisting of,” for example, a composition “comprising” X may consist solely of X or may include something additional, such as X+Y.

[23] As used in this document, the singular forms refer to one or more (e.g., to at least one) grammatical object of the form.

[24] The term "or" is used herein to mean the term "and/or" and is used interchangeably with it unless the context clearly indicates otherwise.

[25] The term “about,” when used with respect to a reference numerical value and its grammatical equivalents, as used herein, may include the numerical value itself and a range of values plus or minus 10% of that numerical value. For example, the quantity “about 10” includes 10 and any quantities from 9 to 11. For example, the term “about,” when used with respect to a reference numerical value, may also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of that value. In some cases, a numerical value disclosed throughout a document may be “approximate” with respect to that numerical value even without a specific mention of the term “about.”

[26] As used herein, the term "baseline" refers to the status of a subject or the severity of a condition, such as a disease or one or more parameters related to the patient's status, observed before treatment, such as before introducing a compound, for example, prior to administration of an ActRII antagonist, optionally in combination with at least one additional therapeutic agent, in accordance with the present invention.

[27] As used herein, the term “administration” in relation to a compound, such as an ActRII antagonist, optionally in combination with at least one additional therapeutic agent, is used to denote delivery of the compound via any delivery route.

[28] The word “essentially” as used in this document does not exclude “entirely”, for example, a composition that is “substantially free” of Y may not contain Y at all. If necessary, the word “substantially” may be excluded from the definition of the present invention.

[29] As used herein, the term “pharmaceutically acceptable” means a non-toxic material that does not substantially interfere with the effectiveness of the biological activity of the active ingredient(s).

[30] The terms "ActRIIA" and "ActRIIB" refer to activin receptors. Activins signal via a heterodimeric receptor serine kinase complex that comprises at least two type I receptors (I and IB) and two type II receptors (IIA and IIB, also called ACVR2A and ACVR2B). All of these receptors are transmembrane proteins consisting of a ligand-binding extracellular domain with a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling, with type II receptors required for ligand binding and for type I receptor expression/recruitment. Type I and II receptors form a stable complex upon ligand binding, resulting in phosphorylation of type I receptors by type II receptors. Activin receptor II B (ActRIIB) is a receptor for myostatin. Activin receptor II A (Act RIIA) is also a receptor for myostatin. The term ActRIIB or Act IIB receptor refers to human ActRIIB (AAC64515.1, GI:3769443). Research-grade polyclonal and monoclonal antibodies to ActRIIB are known in the art, such as those manufactured by R&D Systems ^® , Minnesota, USA. Of course, the antibodies may react with ActRIIB from other species and may be used to treat pathological conditions in these species.

[31] By "ActRII binding molecule" is meant any molecule capable of binding to the human ActRII receptors, which are ActRIIA and/or ActRIIB, either alone or in association with other molecules. Binding may be demonstrated by standard methods (qualitative assays), including, for example, a binding assay, a competition assay, or a bioassay to determine the degree of inhibition of ActRII receptor binding to myostatin, or any type of binding assay compared to a negative control assay using an antibody of unrelated specificity, but ideally of the same isotype, such as an anti-CD25 antibody. Non-limiting examples of ActRII receptor binding molecules include small molecules such as aptamers or other nucleic acid molecules engineered and/or subjected to binding to the receptor, ligand decoys and antibodies to the ActRII receptor produced by B cells or hybridomas, and chimeric antibodies, CDR-grafted antibodies or human antibodies or any fragment thereof, such as F(ab')2 and Fab fragments, and single-chain or single-domain antibodies. Preferably, the ActRII receptor binding molecule antagonizes (e.g., reduces, inhibits, decreases, delays) the binding of natural ligands to the ActRII receptor. Some embodiments of the disclosed methods, regimens, kits, processes and uses utilize an ActRIIB receptor binding molecule.

[32] "Signaling activity" refers to a biochemical causal relationship, typically initiated by a protein-protein interaction, such as the binding of a growth factor to a receptor, resulting in the transmission of a signal from one part of a cell to another part of the cell. Transmission typically involves the specific phosphorylation of one or more tyrosine, serine, or threonine residues in one or more proteins in a series of reactions that mediate signal transduction. The penultimate processes typically involve nuclear events that result in changes in gene expression.

[33] As used in this document, the term "patient" is used interchangeably with the term "subject" and refers to a human patient.

[34] As used herein, a subject is in "need" of treatment if the subject is one who has the pathological condition of interest (i.e., disease or disorder) and who will benefit biologically, medically, or by improving the quality of life as a result of such treatment.

[35] The term "treatment or prevention" includes administration of a compound, such as an ActRII antagonist, preferably bimagrumab, optionally in combination with at least one additional therapeutic agent, to prevent or delay the onset of symptoms, complications or biochemical evidence of a disease (e.g., liver disease or disorder), to reduce the severity of symptoms or to stop or suppress further progression of the disease, condition or disorder. Treatment may be prophylactic (to prevent or delay the onset of the disease or to prevent the manifestation of its clinical or subclinical symptoms) or therapeutic to suppress or reduce the severity of symptoms after the onset of the disease.

[36] As used herein in connection with a disease or disorder, the term "prevent," "preventing," or "prevention" refers to prophylactic treatment of a subject at risk of developing a condition (e.g., a specific disease or disorder or a clinical symptom thereof, such as a liver disease or disorder) that results in a reduction in the likelihood that the subject will develop the condition.

[37] The terms "treat," "treating," and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures that aim to ameliorate the manifestations of a disease or disorder (i.e., slow, arrest, or reduce the progression of the disease or at least one of its clinical symptoms) by reducing the severity or ameliorating the manifestations of at least one physical parameter, including those that may not be perceptible to the patient. The terms "treat," "treating," and "treatment" also refer to modulating the disease or disorder either physically (e.g., by stabilizing an overt symptom) or physiologically (e.g., by stabilizing a physical parameter), or both, and/or preventing or delaying the onset or development or progression of the disease or disorder.

[38] For example, "treating NASH" or "treating NAFLD" may refer to ameliorating, decreasing, or modulating at least one of the symptoms or pathological features associated with NASH/NAFLD; e.g., hepatosteatosis, liver cell ballooning, inflammation, and liver fibrosis; for example, it may refer to slowing the progression of, reducing, or eliminating at least one of the symptoms or pathological features associated with NASH/NAFLD, e.g., hepatosteatosis, liver cell ballooning, inflammation, and liver fibrosis. It may also refer to preventing or delaying the development of liver cirrhosis or the need for liver transplantation, e.g., slowing the progression of, halting, or reversing the progression of the disease and improving clinical outcomes (i.e., preventing progression to cirrhosis and its complications, reducing the need for liver transplantation, and improving survival).

[39] As used herein, the term NAFLD can encompass different stages of the disease: hepatosteatosis or non-alcoholic fatty liver disease (NAFL), NASH, NASH with fibrosis, and NASH with cirrhosis. NASH is typically characterized by hepatic steatosis, ballooning of liver cells, and lobular inflammation. NAFL is characterized by accumulation of triacylglycerol (TAG) in the liver. Hepatic steatosis is defined as a hepatic TAG content of at least 5% of the liver weight or 5% of hepatocytes containing lipid vacuoles, in the absence of a secondary contributing factor such as excess alcohol consumption, viral infection, or drug treatment procedures.

[40] Also, "treatment delivery" of NASH may refer to slowing, halting, or reversing disease progression and improving clinical outcomes, i.e., preventing progression to cirrhosis, and regression of steatohepatitis and no worsening of liver fibrosis as assessed by the NASH Clinical Trials Network (CRN) histology.

[41] Treatment for NASH includes:

- "regression of steatohepatitis", defined as the absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for ballooning and any value for steatosis; complications of cirrhosis, reduced need for liver transplantation and increased survival;

- or improvement in liver fibrosis by one or more stages (NASH CRN histologic score) and no worsening of steatohepatitis (eg, defined as no increase in ballooning, inflammation, or steatosis in NAS);

- or both regression of steatohepatitis and improvement in fibrosis (as defined above).

[42] “Treating” or “treating” NAFLD or NASH in a human subject includes one or more of:

reducing the risk of developing NAFLD or NASH, i.e. preventing the development of clinical symptoms of NAFLD or NASH in a subject who may be predisposed to NAFLD or NASH.

suppression of NAFLD or NASH, i.e., stopping or reducing the development of NAFLD or NASH or their clinical symptoms; and

alleviation of NAFLD or NASH, i.e., providing regression, reversal, or reduction in the intensity of manifestations of NAFLD or NASH or a decrease in the number, frequency, duration, or severity of their clinical symptoms.

[43] The term “NAS score” used in this document refers to the NAFLD activity score, a widely used histologic scoring and staging system for NAFLD (Kleiner et al., Hepatology. 2005 Jun; 41(6):1313-21).

[44] An “effective amount” refers to an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves the desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is an amount necessary to prevent the onset of a disease or symptoms of a disease. An effective amount may be administered by one or more administrations, applications, or dosages. A “therapeutically effective amount” of a therapeutic compound (i.e., an effective dose) depends on the therapeutic compounds selected. The compositions may be administered from one or more times per day to one or more times per week, and may also include less frequent administration, such as, as described herein. One skilled in the art will appreciate that the dose and time frame required to effectively treat a subject may be influenced by certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and the presence of other medical conditions. Furthermore, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein may involve a single treatment procedure or a course of treatment.

[45] As used herein, the term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject, such as ameliorating symptoms, reducing the severity of conditions, slowing or delaying the progression of a disease, or preventing the onset of a disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to that amount of a compound of the present invention that, when administered to a subject, is effective in at least partially ameliorating, suppressing, preventing, and/or ameliorating a condition associated with a liver disease or disorder.

[46] As defined herein, “combination” refers to either a fixed combination in a single unit dosage form (e.g., capsule, tablet, sachet, or vial), a random (i.e., non-fixed) combination, or a kit of parts for combination administration, wherein an ActRII agonist, such as bimagrumab, and one or more additional therapeutic agents are to be administered independently at the same time or separately within time intervals, particularly where those time intervals allow the combination partners to exert a combined, e.g., synergistic, effect.

[47] The terms "co-administration" or "combined administration" or the like, as used herein, are intended to encompass the administration of an additional therapeutic agent to a single subject in need thereof (e.g., a subject) and an additional therapeutic agent, and are intended to include treatment regimens in which an ActRII agonist, such as bimagrumab, and the additional therapeutic agent are optionally administered via the same route of administration and/or at the same time. Each of the components of the combination of the present invention may be administered simultaneously or sequentially and in any order. Co-administration includes simultaneous, sequential, overlapping, spaced, continuous administration, and any combination thereof.

[48] The term "pharmaceutical combination" as used herein means a pharmaceutical composition that is obtained by combining (e.g. mixing) more than one active ingredient, and includes fixed and arbitrary combinations of active ingredients.

[49] The term "fixed combination" means that the active ingredients are administered to the subject simultaneously as a single whole or in measured doses.

[50] The term "random combination (non-fixed combination)" means that the active ingredients defined herein are administered to a subject as separate compounds either simultaneously, in parallel, or sequentially without specific time limitations and in any order, wherein such administration provides therapeutically effective levels of the compounds in the subject's body. In particular, reference to a combination comprising a) activin type II receptor (ActRII) antagonists, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the human ActRII receptor, preferably an antagonist antibody to ActRIIA and/or ActRIIB, most preferably bimagrumab, and b) at least one additional therapeutic agent as used herein (e.g., in any of the embodiments or in any of the claims provided herein) refers to a "non-fixed combination" and may be administered independently at the same time or separately within time intervals.

[51] By "simultaneous administration" is meant that the active ingredients defined in this document are administered on the same day. The active ingredients may be administered at the same time (for fixed or random combinations) or one at a time (for random combinations).

[52] In accordance with the present disclosure, “sequential administration” may mean that over a period of two or more days of continuous co-administration, only one of the active ingredients defined herein is administered on any one day.

[53] By "overlapping administration" is meant that during a period of two or more days of continuous co-administration, there is at least one day of co-administration and at least one day when only one of the active ingredients defined herein is administered.

[54] By "continuous administration" is meant a period of co-administration without any blank day. Continuous administration may be simultaneous, sequential or overlapping as described above.

[55] The term "dose" refers to a specific amount of a drug administered at one time. The dose will, for example, be listed on the drug's packaging or in the instructions for use of the drug.

[56] The term "obesity" is based on BMI for both young people and adults, but the definitions are not directly comparable. For adults, there is a set cutoff value based on health risk, while for children the definition is statistical and based on comparison with a reference population. BMI was calculated as weight in kilograms divided by height in meters squared, rounded to one decimal place. Obesity in adults is defined as a BMI greater than or equal to 30 kg/m ² .

[57] Obesity in young adults is defined as a BMI greater than or equal to the age- and sex-specific 95th percentile according to the 2000 CDC growth charts.

[58] The term "overweight status" is based on a BMI of ≥ 25 to < 30 kg/m ² .

[59] Being overweight may also be associated with at least one additional risk factor for fatal diseases (stroke, MI, heart failure, sudden death), such as diabetes mellitus, hypertension, family history of early coronary artery disease, etc.

[60] Because different subjects may have the same BMI but different percentages of fat and muscle mass, BMI is not always an appropriate measure for classifying overweight and obesity. A high percentage of muscle mass may result in a high BMI even with a low percentage of fat; in this case, a subject may be incorrectly considered overweight or obese based on BMI classification. In addition to BMI, other indices are used, namely waist circumference and body shape index (ABSI); imaging with dual-energy X-ray absorptiometry (DXA or DEXA) and magnetic resonance imaging (MRI) is often used to quantify the percentage of muscle, fat, and fat distribution.

[61] The term "body composition" is used in this document to describe the percentage of fat and muscle in people's bodies. Since muscle tissue takes up less space in our bodies than fat tissue, our body composition, as well as our weight, determines how lean we are.

[62] "Lean body mass" is a component of body composition calculated by subtracting fat mass from total body weight, where total body weight is equal to the sum of lean mass and fat mass.

[63] From the equations it follows:

LBM=BW - BF,

Lean body mass is equal to body weight minus body fat;

LBM+BF=BW,

Lean body mass plus body fat equals body weight.

The percentage of total body mass that is lean is not usually reported - it is usually 60-90%. Instead, the percentage of body fat is calculated, which is in addition and is usually 10-40%. Lean body mass (LBM) has been described as superior to total body weight for prescribing appropriate drug dosage levels and for assessing metabolic disorders, since body fat is less metabolically significant.

[64] The term "fat mass" refers to the portion of the human body that is composed solely of fat. It can be measured using DXA, MRI, or bioelectrical impedance techniques.

[65] The term "central obesity" refers to the following: obesity is defined as a condition characterized by abnormal or excessive accumulation of fat in adipose tissue. The absolute amount of excess fat and its regional distribution among different fat depots play an important role in determining the impact of obesity on health. Obesity can be divided into central/android obesity and peripheral/gynoid obesity, with android obesity being more common in men and gynoid obesity being more common in women.

[66] There is substantial evidence in the literature indicating that not all types of obesity are associated with an unfavorable metabolic profile and increased cardiovascular risk. In fact, body fat distribution (i.e. the relative presence of abdominal and peripheral fat mass) has been considered a better indicator of metabolic and cardiovascular risks than the degree of obesity per se. In men, who tend to accumulate fat in the trunk area, increased BMI is associated with increased cardiovascular risk, while in women, increased BMI is generally a poor indicator/surrogate for cardiovascular risk.

[67] Trunk fat mass can be divided into subcutaneous (SC) fat (in the abdominal wall) and visceral adipose tissue (in the intra-abdominal cavity). Subcutaneous and visceral fat differ significantly in their anatomical characteristics, cellular composition, endocrine function, and cellular regulation. VAT is characterized by higher cellularity, vascularity, levels of innervation, and inflammatory and immune cell infiltration than SC, resulting in higher metabolic activity and increased release of proinflammatory cytokines with direct and indirect consequences for insulin resistance, type 2 diabetes, and cardiovascular disease risk. In contrast, subcutaneous fat mass, particularly thigh and buttock fat depots, has been associated with constitutive secretion of adiponectin, which has insulin-sensitizing, anti-inflammatory, and antiatherogenic effects. Low-grade inflammation has been linked to muscle wasting, which in turn may further worsen insulin sensitivity and increase the relative risk of developing type 2 diabetes.

[68] Thus, an imbalance between central and peripheral fat depots (central obesity), even in the absence of severe obesity (i.e. BMI <30 kg/ ^m2 ), may be associated with severe insulin resistance, metabolic changes, and systemic nonspecific inflammation, which together lead to accelerated atherogenesis.

[69] The term "type II diabetes mellitus", also referred to as type 2 diabetes mellitus, previously called "non-insulin-dependent diabetes mellitus" or "maturity-onset diabetes mellitus", accounts for 90-95% of all cases of diabetes mellitus, and includes individuals who have insulin resistance and usually a relative (rather than absolute) insulin deficiency. At least initially, and often throughout their life, such individuals may not require insulin treatment to maintain life. There are various causes of type 2 diabetes mellitus.

[70] "Insulin sensitivity" describes how sensitive the body is to the effects of insulin. A person who is said to have high insulin sensitivity will require less insulin to lower blood glucose levels than a person who is said to have low sensitivity. Insulin sensitivity varies from person to person, and doctors can perform tests to determine an individual's sensitivity to insulin.

[71] "Insulin resistance" is defined as a condition characterized by tolerance to insulin, in which the hormone becomes less effective, causing decreased glucose uptake into muscle tissue, resulting in impaired glucose oxidation and glycogen synthesis, and inadequate suppression of hepatic glucose production. In obesity, increased visceral fat mass with elevated plasma free fatty acid (FFA) levels due to increased lipolytic activity worsens insulin resistance by impairing insulin action, a mechanism known as lipotoxicity.

[72] “Antidiabetic treatment” for type 2 diabetes includes the following:

Metformin . Metformin is usually the first drug prescribed for type 2 diabetes. It works by increasing the sensitivity of the body's tissues to insulin, allowing the body to use insulin more efficiently. Metformin also reduces the production of glucose in the liver. Metformin alone may not lower blood sugar levels sufficiently.

Dipeptidyl peptidase-4 (DPP-4) inhibitors: These medications also lower blood sugar levels. They do not cause weight gain. Examples of these medications include sitagliptin, saxagliptin, vildagliptin, and linagliptin.

Sulfonylureas : These medications cause the body to secrete more insulin. Examples of medications in this class include glyburide, glipizide, and glimepiride. Possible side effects include low blood sugar and weight gain.

Thiazolidinediones . Like metformin, these drugs make the body's tissues more sensitive to insulin. This class of drugs is associated with weight gain and other more serious side effects, such as an increased risk of heart failure and fractures. Because of these risks, these drugs are not usually first-line treatments. Pioglitazone is an example of a thiazolidinedione.

GLP-1 receptor agonists (GLP-1Ra) . These drugs slow down digestion and help lower blood sugar levels. They are often associated with some weight loss. This class of drugs is not recommended for use alone. Examples of GLP-1 receptor agonists include exenatide, semaglutide, and liraglutide.

SGLT2 inhibitors. These are the newest diabetes drugs on the market. They work by preventing the kidneys from absorbing sugar into the blood. Instead, the sugar is excreted in the urine. Examples include canagliflozin and dapagliflozin.

Insulin therapy. Some people with type 2 diabetes also require insulin therapy. In the past, insulin therapy was used as a last resort, but today it is often prescribed earlier due to its benefits.

[73] As used herein, the term "antibody" as defined herein includes complete antibodies and any antigen-binding fragment thereof or individual chains thereof (i.e., an "antigen-binding portion" or "functional fragment"). A naturally occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V _H ) and a heavy chain constant region. The heavy chain constant region is comprised of three domains: CH1, CH2, and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as V _L ) and a light chain constant region. The light chain constant region is comprised of a single domain, referred to as _CL . The V _H and V _L regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), which alternate with more conserved regions called framework regions (FRs). Each V _H and V _L is formed by three CDRs and four FRs, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain the binding domain that interacts with antigen. The constant regions of antibodies can mediate binding of immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement pathway.

[74] As used herein, the term "functional fragment" of an antibody refers to portions or fragments of an antibody that retain the ability to specifically bind an antigen (e.g., a portion of ActRIIB). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "functional fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the V _L , V _H , CL, and CH1 domains; an F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; an Fd fragment, consisting of the V _H and CH1 domains; an Fv fragment, consisting of the V _L and V _H domains of one arm of an antibody; a dAb fragment (Ward et al., 1989), which consists of the V _H domain; and an isolated complementarity determining region (CDR). Although the two domains of the Fv fragment, V _L and V _H, are encoded by separate genes, they can be combined using recombinant techniques by means of a synthetic linker that allows them to be produced as a single protein chain in which the V _L and V _H regions are paired to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., 1988; and Huston et al., 1988). It is also envisaged that such single-chain antibodies are encompassed by the term "functional fragments" of an antibody. These antibody fragments are produced by conventional techniques known to those skilled in the art and the fragments are screened for suitability in the same manner as intact antibodies.

[75] As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single type of binding specificity and affinity for a particular epitope.

[76] As used herein, the term "human antibody" as used herein includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences derived from a human. Additionally, if the antibody comprises a constant region, the constant region is also derived from such human sequences, such as human germline sequences, or mutant variants of human germline sequences, or an antibody comprising framework region consensus sequences obtained by analyzing human framework region sequences as described in Knappik, et al . (2000). J Mol Biol 296, 57-86. A "human antibody" need not be produced by a human, human tissue, or human cell. The human antibodies of the present invention may comprise amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo ). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from a germline antibody of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[77] The term "recombinant human antibody" as used herein includes all human antibodies that are produced, expressed, created, or isolated by recombinant methods, such as antibodies isolated from an animal (e.g., mouse) that is transgenic or transchromosomal for human immunoglobulin genes, or a hybridoma derived therefrom, antibodies isolated from a host cell transformed to express a human antibody, such as from a transfectoma, antibodies isolated from a recombinant combinatorial library of human antibodies, and antibodies produced, expressed, generated, or isolated by any other methods that involve splicing all or part of a human immunoglobulin gene sequence into other DNA sequences. Such recombinant human antibodies comprise variable regions in which the framework regions and CDR regions are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be subjected to mutagenesisin vitro(or, in the case of using an animal transgenic for human Ig sequences, somatic mutagenesisin vivo) and thus the amino acid sequences of V_H- and V_L-regions of recombinant antibodies are sequences that, although derived from V sequences_Hand V_Lhuman germline antibodies or related to them may not naturally exist in the human germline antibody repertoirein vivo.

[78] As used herein, the term "an antibody that binds to an ActRIIB polypeptide" is intended to refer to an antibody that binds to a human ActRIIB polypeptide with a _KD of about 100 nM or less, about 10 nM or less, or about 1 nM or less. As used herein, the term " _KD " as used herein is intended to refer to a dissociation constant that is derived from the ratio of _Kd to _Ka (i.e., _Kd / _Ka ) and that is expressed as a molar concentration (M). _KD values for antibodies can be determined by methods well known in the art. A method for determining the _KD of an antibody is carried out using surface plasmon resonance or using a biosensor system such as the Biacore® system or by titration at equilibrium in solution.

[79] As used herein, the term "antagonist antibody" is intended to refer to an antibody that suppresses ActRIIB-induced signaling activity in the presence of myostatin or other ActRIIB ligands such as activins or GDF-11, and/or an antibody that suppresses ActRIIA-induced signaling activity in the presence of myostatin or other ActRIIA ligands such as activins or GDF-11. Examples of assays for detecting this include suppression of myostatin-induced signaling (e.g., using a Smad-dependent reporter gene assay), suppression of myostatin-induced Smad phosphorylation (P-Smad ELISA), and suppression of myostatin-induced suppression of skeletal muscle cell differentiation (e.g., using a creatine kinase assay).

[80] In some embodiments, antibodies that bind to an ActRIIB polypeptide suppress myostatin-induced signaling, as measured by a Smad-dependent reporter gene assay, with an IC ₅₀ of about 10 nM or less, about 1 nM or less, or about 100 pM or less.

[81] The term "testing" as used herein means that a sample may be tested (either directly or indirectly) for either the presence or level of a given marker (e.g. hsCRP and/or haemoglobin). It will be appreciated that where the level of a substance is indicative of a probability, the level of that substance may be used as a basis for selecting a treatment. For example, the level of hsCRP and/or haemoglobin in a patient may be determined by testing for its presence using quantitative or comparative qualitative methods (e.g. levels compared to levels in other samples).

ActRII antagonists

[82] Various disclosed uses, methods, combinations, and kits utilize an ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist, such as an anti-ActRII receptor antibody, such as an anti-ActRII receptor antibody that is bimagrumab. In some embodiments, the ActRII antagonist is an ActRIIA and/or ActRIIB antagonist, preferably an anti-ActRII receptor antibody or antigen-binding fragment thereof.

[83] In one embodiment, an antibody to an ActRII receptor or antigen-binding fragment thereof comprises at least one variable domain of a heavy chain (VH) of an immunoglobulin comprising hypervariable regions CDR1, CDR2, and CDR3, wherein said CDR1 is characterized by the amino acid sequence of SEQ ID NO:1, said CDR2 is characterized by the amino acid sequence of SEQ ID NO:2, and said CDR3 is characterized by the amino acid sequence of SEQ ID NO:3. In one embodiment, an antibody to an ActRII receptor or antigen-binding fragment thereof comprises at least one variable domain of a light chain (VL') of an immunoglobulin comprising hypervariable regions CDR1', CDR2' and CDR3', wherein said CDR1' is characterized by the amino acid sequence of SEQ ID NO:4, said CDR2' is characterized by the amino acid sequence of SEQ ID NO:5, and said CDR3' is characterized by the amino acid sequence of SEQ ID NO:6.

[84] In one embodiment, an anti-ActRII receptor antibody or antigen-binding fragment thereof comprises at least one immunoglobulin V _H domain and at least one immunoglobulin V _L domain, wherein a) the immunoglobulin V _H domain comprises (e.g., in sequential order) i) hypervariable regions CDR1, CDR2, and CDR3, wherein said CDR1 is characterized by the amino acid sequence of SEQ ID NO:1, said CDR2 is characterized by the amino acid sequence of SEQ ID NO:2, and said CDR3 is characterized by the amino acid sequence of SEQ ID NO:3; and b) the V _L domain of the immunoglobulin comprises (e.g., in sequential order) hypervariable regions CDR1', CDR2' and CDR3', wherein said CDR1' is characterized by the amino acid sequence of SEQ ID NO:4, said CDR2' is characterized by the amino acid sequence of SEQ ID NO:5, and said CDR3' is characterized by the amino acid sequence of SEQ ID NO:6.

[85] In one embodiment, an anti-ActRII receptor antibody or antigen-binding fragment thereof comprises a) an immunoglobulin heavy chain variable domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:10; b) an immunoglobulin light chain variable domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:9; c) an immunoglobulin VH domain comprising the amino acid sequence set forth in SEQ ID NO:10 and an immunoglobulin VL domain comprising the amino acid sequence set forth in SEQ ID NO:9; d) an immunoglobulin VH domain comprising the hypervariable regions set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; e) an immunoglobulin VL domain comprising the hypervariable regions set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6; or f) an immunoglobulin VH domain comprising the hypervariable regions set forth in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 and an immunoglobulin VL domain comprising the hypervariable regions set forth in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

[86] For ease of searching, the amino acid sequences of the monoclonal antibody bimagrumab are presented in Table 1.

Table 1. Sequence information for bimagrumab SEQ ID NO: Description of the sequence Detailed amino acid or nucleotide sequence 1 Heavy chain CDR1 GYTFTSSYIN 2 Heavy chain CDR2 TINPVSGSTSYAQKFQG 3 Heavy chain CDR3 GGWFDY 4 CDR1' light chain TGTSSDVGSYNYVN 5 CDR2' light chain LMIYGVSKRPS 6 CDR3' light chain GTFAGGSYYG 7 Light chain (LC) QSALTQPASVSGSPGQSITISCTGTSSDVGSYNYVNWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCGTFAGGSYYGVFGGGTKL TVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 8 Heavy Chain (HC) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSSYINWVRQAPGQGLEWMGTINPVSGSTSYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGGWFDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 9 Variable region of the light chain (VL) QSALTQPASVSGSPGQSITISCTGTSSDVGSYNYVNWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCGTFAGGSYYGVFGGGTKLTVL 10 Variable region of the heavy chain (VH) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSSYINWVRQAPGQGLEWMGTINPVSGSTSYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGGWFDYWGQGTLVTVSS

[87] In preferred embodiments, the constant region domains also include suitable human constant region domains, such as those described in “Sequences of Proteins of Immunological Interest,” Kabat E.A. et al, US Department of Health and Human Services, Public Health Service, National Institute of Health.

[88] In some embodiments, the anti-ActRII receptor antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO:7. In other embodiments, the anti-ActRII receptor antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO:8. In other embodiments, the anti-ActRII receptor antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO:7 and the heavy chain of SEQ ID NO:8. In some embodiments, the anti-ActRII receptor antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:7. In other embodiments, the anti-ActRII receptor antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:8. In other embodiments, the anti-ActRII receptor antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:7 and the three CDRs of SEQ ID NO:8. The CDRs of SEQ ID NO:7 and SEQ ID NO:8 can be found in Table 1.

[89] In one embodiment, the anti-ActRII receptor antibody or antigen-binding fragment thereof (e.g., bimagrumab) is selected from an anti-human ActRII receptor antibody that comprises at least a) an immunoglobulin heavy chain or fragment thereof that comprises a variable domain comprising, in sequential order, the hypervariable regions CDR1, CDR2, and CDR3 and a constant portion or fragment thereof from a human heavy chain; wherein said CDR1 is characterized by the amino acid sequence of SEQ ID NO:1, said CDR2 is characterized by the amino acid sequence of SEQ ID NO:2, and said CDR3 is characterized by the amino acid sequence of SEQ ID NO:3; and b) an immunoglobulin light chain or fragment thereof that comprises a variable domain comprising, in sequential order, the hypervariable regions CDR1', CDR2', and CDR3' and a constant portion or fragment thereof from a human light chain; wherein said CDR1' is characterized by the amino acid sequence of SEQ ID NO:4, said CDR2' is characterized by the amino acid sequence of SEQ ID NO:5, and said CDR3' is characterized by the amino acid sequence of SEQ ID NO:6.

[90] In one embodiment, the anti-ActRII receptor antibody or antigen-binding fragment thereof is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen-binding site comprising a) a first domain comprising, in sequential order, the hypervariable regions CDR1, CDR2, and CDR3, wherein said CDR1 is characterized by the amino acid sequence of SEQ ID NO:1, said CDR2 is characterized by the amino acid sequence of SEQ ID NO:2, and said CDR3 is characterized by the amino acid sequence of SEQ ID NO:3; and b) a second domain comprising, in sequential order, the hypervariable regions CDR1', CDR2', and CDR3', wherein said CDR1' is characterized by the amino acid sequence of SEQ ID NO:4, said CDR2' is characterized by the amino acid sequence of SEQ ID NO:5, and said CDR3' is characterized by the amino acid sequence of SEQ ID NO:6; and c) a peptide linker that is linked to either the N-terminal end of the first domain and the C-terminal end of the second domain, or the C-terminal end of the first domain and the N-terminal end of the second domain.

[91] Alternatively, an anti-ActRII receptor antibody or antigen-binding fragment thereof used in the disclosed methods may comprise a derivative of the anti-ActRII receptor antibodies sequenced herein (e.g., pegylated variants, glycosylation variants, affinity maturation variants, etc.). Alternatively, the V _H or V _L domains of an anti-ActRII receptor antibody or antigen-binding fragment thereof used in the disclosed methods may comprise V _H or V _L domains that are substantially identical to the V _H or V _L domains set forth herein (e.g., set forth in SEQ ID NOs:10 and 9). An anti-human ActRII receptor antibody disclosed herein may comprise a heavy chain that is substantially identical to the chain set forth in SEQ ID NO:8 and/or a light chain that is substantially identical to the chain set forth in SEQ ID NO:7. An anti-human ActRII receptor antibody disclosed herein may comprise a heavy chain that provides SEQ ID NO:8 and a light chain that provides SEQ ID NO:7. An anti-human ActRII receptor antibody disclosed herein may comprise a) one heavy chain comprising a variable domain characterized by an amino acid sequence substantially identical to the sequence shown by SEQ ID NO:10 and a constant portion of a human heavy chain; and b) one light chain comprising a variable domain characterized by an amino acid sequence substantially identical to the sequence shown by SEQ ID NO:9 and a constant portion of a human light chain.

[92] Alternatively, an anti-ActRII receptor antibody or antigen-binding fragment thereof used in the disclosed methods may be an amino acid sequence variant of the reference anti-ActRII receptor antibodies set forth herein. The present disclosure also includes anti-ActRII receptor antibodies or antigen-binding fragments thereof (e.g., bimagrumab) in which one or more amino acid residues of the VH or VL domain of bimagrumab, typically only a few (e.g., 1-10), are altered; for example, by mutation, such as site-directed mutagenesis of the corresponding DNA sequences.

[93] In some embodiments, an anti-ActRII antibody, e.g., bimagrumab, binds to an epitope of a human ActRII receptor comprising WLDDFN (SEQ ID NO:11). In some embodiments, anti-ActRII antibodies or antigen-binding fragments thereof, e.g., bimagrumab, bind to an epitope of a human ActRII receptor comprising GCWLDDFNC (SEQ ID NO:12). In some embodiments, an anti-ActRII antibody, e.g., bimagrumab, binds to an epitope of a human ActRII receptor comprising KGCWLDDFNCY (SEQ ID NO:13). In some embodiments, an anti-ActRII antibody, e.g., bimagrumab, binds to an epitope of a human ActRII receptor comprising EQDKR (SEQ ID NO:14). In some embodiments, an anti-ActRII antibody, e.g., bimagrumab, binds to an epitope of a human ActRII receptor comprising CEGEQDKRLHCYASW (SEQ ID NO:15). In some embodiments, an anti-ActRII antibody, e.g., bimagrumab, binds to an epitope of a human ActRII receptor comprising WLDDFN (SEQ ID NO:11), CEGEQDKRLHCYASW (SEQ ID NO:15), and GCWLDDFNC (SEQ ID NO:12). In some embodiments, an anti-ActRII antibody, e.g., bimagrumab, binds to an epitope of a human ActRII receptor comprising WLDDFN (SEQ ID NO:11) and CEGEQDKRLHCYASW (SEQ ID NO:15). In some embodiments, an anti-ActRII antibody, such as bimagrumab, binds to an epitope of a human ActRII receptor comprising WLDDFN (SEQ ID NO:11) and EQDKR (SEQ ID NO:14). In some embodiments, an anti-ActRII antibody has a _KD of about 2-10 pM relative to human ActRIIB and a KD of about 100-600 pM relative to human ActRIIA (e.g., as determined by a Biacore® assay).

[94] In a particularly preferred embodiment of any of the disclosed uses, methods, combinations, and kits, the ActRII antagonist is bimagrumab. Bimagrumab has been described in WO 2010/125003, which is hereby incorporated by reference in its entirety.

[95] Bimagrumab, a pharmaceutically active compound used in accordance with the present invention, is a fully human monoclonal antibody (modified IgG1, 234-235-Ala-Ala, λ2) designed to competitively bind to the activin type II receptor (ActRII) with higher affinity than its natural ligands, including myostatin and activin. Bimagrumab is cross-reactive with human and mouse ActRIIA and ActRIIB and is effective in human, cynomolgus monkey, mouse, and rat skeletal muscle cells. Bimagrumab binds with extremely high affinity (KD 1.7 ± 0.3 pM) to human ActRIIB and with relatively lower affinity to human ActRIIA (KD 434 ± 25 pM).

[96] Bimagrumab comprises an antigen-binding site comprising at least one immunoglobulin heavy chain variable domain (V _H ) that comprises, in sequential order, hypervariable regions comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3. The use of antibodies having 1, 2, or 3 residues altered from any of the heavy chain CDR1, CDR2, and/or CDR3 sequences is also encompassed within the scope of the present disclosure.

[97] Bimagrumab also comprises an antigen-binding site comprising at least one immunoglobulin light chain variable domain (V _L ) that comprises, in sequential order, hypervariable regions comprising CDR1' of SEQ ID NO: 4, CDR2' of SEQ ID NO: 5, and CDR3' of SEQ ID NO: 6, or equivalent CDRs.

[98] The use of antibodies having 1, 2 or 3 residues altered relative to any of the CDR1', CDR2' and/or CDR3' sequences of the light chain is also encompassed within the scope of the present disclosure.

[99] The present disclosure also provides for the use of antibodies having 95% amino acid sequence identity to the light chain and/or heavy chain of bimagrumab.

[100] The sequence listing for bimagrumab is provided in this document.

[101] Other preferred ActRII antagonists for use in accordance with the disclosed uses, methods, combinations, and kits are described in U.S. Patent No. 7,893,213, WO 2017147182, WO 2016069234, WO 2006012627, WO 9956768, WO 2002010214, WO 2006012627, which are incorporated herein by reference in their entireties.

Applications and methods

[102] The present invention arises in part from the results of an analysis of data obtained during the clinical trial with the ClinicalTrials.gov identifier: NCT03005288 and disclosed in WO 2018/116201 (the contents of which are hereby incorporated by reference in its entirety), which is a randomized, blinded subject and investigator, placebo-controlled study to evaluate the safety, pharmacokinetics and efficacy of intravenous bimagrumab in overweight and obese patients with type 2 diabetes mellitus. The study enrolled 75 patients with type 2 diabetes mellitus, HbA1c levels from 6.5% to 10% and a body mass index from 28 to 40 kg/m ² at the time of screening. Bimagrumab was administered every four weeks at a dose of 10 mg/kg with a maximum dose of 1200 mg intravenously administered in 12 doses and compared with placebo.

[103] The present inventors have found that treatment with an antibody to ActRII, such as bimagrumab, provides a significant reduction in liver fat fraction. Accordingly, activin type II receptor (ActRII) antagonists, such as molecules capable of antagonizing the binding of activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and/or myostatin to the human ActRII receptor, preferably an antagonist antibody to ActRIIA and/or ActRIIB, most preferably bimagrumab, can be used according to the present invention for the prevention or treatment of a liver disease or disorder, in particular a liver disease or disorder associated with increased liver fat, such as associated with hepatic steatosis.

[104] Various (numbered) embodiments of the present invention are described herein. It should be understood that the features described in each embodiment can be combined with other described features to produce additional embodiments of the present invention.

Implementation options (a)

1a. An activin type II receptor antagonist (ActRII) for use in the treatment of a liver disease or disorder in a subject in need thereof.

2a. An activin type II receptor antagonist (ActRII) for use in the prevention of liver disease or disorder in a subject in need thereof.

3a. An activin type II receptor antagonist (ActRII) for use in the treatment, stabilization, or reduction in the severity or progression of non-alcoholic fatty liver disease (NAFLD), such as NASH, in a subject in need thereof, comprising administering an activin type II receptor antagonist (ActRII) in a therapeutically effective amount.

4a. An activin type II receptor antagonist (ActRII) for use in slowing, halting, or reducing the progression of a chronic liver disease or disorder, such as NAFLD, non-alcoholic steatohepatitis (NASH), or liver fibrosis in a subject in need thereof, comprising administering an activin type II receptor antagonist (ActRII) in a therapeutically effective amount.

5a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-4a, wherein said subject has at least one condition selected from hepatic steatosis, lobular inflammation, and hepatic ballooning.

6a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-5a, wherein said subject has hepatic steatosis.

7a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-6a, wherein said liver disease or disorder is selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

8a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-7a, wherein said liver disease or disorder is steatohepatitis.

9a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-8a, wherein said liver disease or disorder is liver fibrosis.

10a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-9a, wherein said liver disease or disorder is non-alcoholic fatty liver disease (NAFLD).

11a. An ActRII antagonist for use according to any one of embodiments 1a-10a, wherein said liver disease or disorder is non-alcoholic steatohepatitis (NASH).

12a. An ActRII antagonist for use according to any one of embodiments 1a-11a, wherein said liver disease or disorder is non-alcoholic steatohepatitis (NASH), and wherein the severity of NASH is mild or moderate with fibrosis level F2-F3.

13a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-12a, wherein administering a therapeutically effective amount of an ActRIIA/ActRIIB antagonist to said subject provides a decrease in liver fat fraction in said subject compared to the liver fat fraction in said subject prior to administering the therapeutically effective amount of the ActRIIA/ActRIIB antagonist.

14a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-13a, wherein administration of a therapeutically effective amount of the ActRIIA/ActRIIB antagonist to said subject provides a reduction in the degree of steatohepatitis compared to the degree of steatohepatitis present prior to administration of the ActRII antagonist.

15a. An activin type II receptor (ActRII) antagonist for use according to any one of embodiments 1a-14a, wherein administration of a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides relief of steatohepatitis.

16a. An activin type II receptor (ActRII) antagonist for use according to any one of embodiments 1a-15a, wherein administration of a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides an improvement in liver fibrosis.

17a. An activin type II receptor (ActRII) antagonist for use according to any one of embodiments 1a-16a, wherein administration of a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides relief of steatohepatitis and improvement in liver fibrosis.

18a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-17a, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in the severity or a reduction in the progression of NASH.

19a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-18a, wherein administration of a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides an improvement in liver fibrosis by at least one stage compared to the stage of liver fibrosis present prior to administration of said ActRIIA/ActRIIB antagonist.

20a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-19a, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist halts the progression of liver fibrosis to stage F3 or F4.

21a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-20a, wherein administration of a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in the NAFLD activity score (NAS) by at least 1 point, by at least 2 points, or by at least 3 points.

22a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-21a, wherein administration of a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in at least one of hepatosteatosis, liver inflammation, and hepatic ballooning by at least 1 NAS point.

23a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-22a, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in at least two of steatosis, liver inflammation, and liver cell ballooning, such as hepatosteatosis and liver inflammation, or hepatosteatosis and liver cell ballooning, or liver cell ballooning and liver inflammation, by at least one NAS score.

24a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-23a, wherein said subject is a subject with diabetes mellitus, a subject with obesity, or a subject with metabolic syndrome or other metabolic disorder.

25a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-24a, wherein said subject has type 2 diabetes mellitus.

26a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-25a, wherein said subject is concurrently receiving a standard treatment for type 2 diabetes mellitus.

27a. An ActRIIA/ActRIIB antagonist for use according to embodiment 26a, wherein the standard treatment agent is selected from metformin, a DPP4 inhibitor, metformin/DPP4 inhibitor, sulfonylureas, thiazolidinediones, GLP-1 receptor agonists, SGLT2 inhibitors, insulin therapy.

28a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-27a, wherein said subject has an HbA1c level of from 6.5% to 10%.

29a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-28a, wherein said subject is obese or overweight or has a normal BMI.

30a. An activin type II receptor antagonist (ActRII) for use according to any one of embodiments 1a-29a, wherein the activin type II receptor antagonist (ActRII) is an ActRIIA and/or ActRIIB antagonist.

31a. An activin type II receptor antagonist (ActRII) for use according to any one of embodiments 1a-30a, wherein the activin type II receptor antagonist (ActRII) is an ActRIIA and ActRIIB antagonist.

32a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-31a, wherein the ActRIIA/ActRIIB antagonist is an anti-ActRII antibody or a functional fragment thereof.

32a. The anti-ActRIIA/ActRIIB antibody of embodiment 31a, wherein said antibody or functional fragment thereof has a Kd of less than 1 nM for ActRIIA and less than 20 pM for ActRIIB.

33a. An ActRIIA/ActRIIB binding antibody or functional fragment thereof according to embodiment 32a, wherein said ActRIIA/ActRIIB binding antibody is selected from the group consisting of:

a) an antibody comprising three CDRs under SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3;

b) an antibody comprising three CDRs under SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6;

c) an antibody comprising three CDRs under SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and three CDRs under SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6;

d) an ActRIIA/ActRIIB binding antibody comprising an HC domain having SEQ ID NO:8;

e) an ActRIIA/ActRIIB binding antibody comprising an LC domain having SEQ ID NO:7;

f) An ActRIIA/ActRIIB binding antibody comprising an HC domain comprising SEQ ID NO:8 and an LC domain comprising SEQ ID NO:7,

g) an ActRIIA/ActRIIB binding antibody comprising a VL domain comprising SEQ ID NO:9,

h) an ActRIIA/ActRIIB binding antibody comprising a VH domain comprising SEQ ID NO:10,

i) An ActRIIA/ActRIIB binding antibody comprising a VL domain comprising SEQ ID NO:9 and a VH domain comprising SEQ ID NO:10,

j) an antibody capable of binding to each of the following epitopes in ActRIIB:

(i) WLDDFN (SEQ ID NO:11) and

(ii) CEGEQDKRLHCYASW (SEQ ID NO:15),

k) an antibody capable of binding to each of the following epitopes in ActRIIB:

(i) WLDDFN (SEQ ID NO:11),

(ii) CEGEQDKRLHCYASW (SEQ ID NO:15) and

(iii) GCWLDDFNC (SEQ ID NO:12),

j) an antibody that:

(i) is capable of binding to an epitope consisting of WLDDFN (SEQ ID NO:11), and

(ii) is capable of binding to an epitope consisting of CEGEQDKRLHCYASW (SEQ ID NO:15).

34a. An ActRIIA/ActRIIB binding antibody or functional fragment thereof according to embodiment 33a, wherein the 3 CDRs of SEQ ID NO:10 are set forth under SEQ ID NOs:1, 2, and 3, and wherein the 3 CDRs of SEQ ID NO:9 are set forth under SEQ ID NOs:4, 5, and 6.

35a. An ActRIIA/ActRIIB binding antibody or functional fragment thereof according to any one of embodiments 33a or 34a, wherein the 3 CDRs of SEQ ID NO:8 are set forth under SEQ ID NO:1, 2, and 3, and wherein the 3 CDRs of SEQ ID NO:7 are set forth under SEQ ID NO:4, 5, and 6.

36a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-35a, wherein the ActRIIA/ActRIIB antagonist is bimagrumab.

37a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-36a comprising administering bimagrumab in an amount of from about 3 mg/kg to about 10 mg/kg.

38a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-37a, wherein bimagrumab is administered at about 3 mg/kg.

39a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-38a, wherein bimagrumab is administered at about 4 mg/kg.

40a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-39a, wherein bimagrumab is administered at about 5 mg/kg.

41a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-40a, wherein bimagrumab is administered at about 6 mg/kg.

42a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-41a comprising administering bimagrumab at about 7 mg/kg.

43a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-42a, wherein bimagrumab is administered at about 8 mg/kg.

44a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-43a, wherein bimagrumab is administered at about 9 mg/kg.

45a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-44a comprising administering bimagrumab at about 10 mg/kg.

46a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-45a wherein bimagrumab is administered every 4 weeks.

47a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-46a, wherein bimagrumab is administered every 4 weeks for at least 3 months, at least 6 months, at least 9 months, or at least 12 months.

48a. An ActRIIA/ActRIIB antagonist for use according to any one of embodiments 1a-47a, wherein at least one additional therapeutic agent is administered.

49a. An ActRIIA/ActRIIB antagonist for use according to embodiment 48a, which comprises administering the ActRIIA/ActRIIB antagonist in combination with at least one additional therapeutic agent for the treatment or prevention of liver disease.

50a. An ActRIIA/ActRIIB antagonist for use in embodiment 49a wherein the at least one additional therapeutic agent is an FXR agonist (e.g., tropifexor, nidufexor, obeticholic acid (6α-ethylchenodeoxycholic acid), cilofexor (GS-9674, Px-102), TERN-101 (LY2562175), EYP001 (PXL007), EDP-305, AKN-083 (Allergan), INT-787 (Intercept), INT-767 (Intercept), AGN-242256 (Allergan), MET409 (Metacrine), a steroyl-CoA desaturase-1 (SCD-1) inhibitor (e.g., arachidyl amidocholanic acid (Aramchol™)), a THR-β agonist (eg, MGL-3196 (resmetirom), VK-2809, MGL-3745 (Madrigal)), galectin-2 inhibitor (eg, GR-MD-02/belapectin), PPAR agonist (eg, saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, IVA337 (Inventiva), CER-002 (Cerenis), GLP-1 agonist (eg, exenatide, liraglutide, semaglutide, NC-101 (Naia Metabolic), G-49 (Astrazeneca), ZP2929 (BI/Zealand), PB-718 (Peg Bio), FGF agonist (eg, pegbelfermin (ARX618), BMS-986171, NGM-282, NGM-313, YH25724, tirzepatide, pyruvate synthase inhibitors (eg, nitazoxanide), apoptotic signal-regulated kinase 1 (ASK1) inhibitor (eg, selonsertib (GS-4997), GS-444217), acetyl-CoA carboxylase (ACC) inhibitor (eg, firsocostat (GS-0976), PF-05221304, gemcaben (Gemphire)), FXR agonist (M480 (Metacrine), NTX-023-1 (Ardelyx), INV-33 (Innovimmune)), a CCR inhibitor (eg, AD-114 (AdAlta), bertilimumab (Immune), CM-101 (ChemomAb), CCX-872 (ChemoCentryx), cenicriviroc), a thiazolidinedione (eg, MSDC-0602K, pioglitazone), a sodium-glucose cotransporter 2/1 (SGLT1/2) inhibitor (eg, remogliflozin, luseogliflozin, dapagliflozin), a DPP-4 inhibitor (sitagliptin, saxagliptin, vildagliptin, linagliptin, evogliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, gosogliptin, dutogliptin), or any combination thereof.

Embodiments (b)

1b. A method of treating a liver disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an activin type II receptor antagonist (ActRII).

2b. A method for preventing a liver disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an activin type II receptor antagonist (ActRII).

3b. A method for treating, stabilizing, or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD), such as NASH, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an activin type II receptor antagonist (ActRII).

4b. A method for slowing, stopping, or reducing the progression of a chronic liver disease or disorder, such as NAFLD, non-alcoholic steatohepatitis (NASH), or liver fibrosis, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an activin type II receptor antagonist (ActRII).

5b. The method according to any one of embodiments 1b-4b, wherein said subject has at least one condition selected from hepatic steatosis, lobular inflammation, and hepatic ballooning.

6b. The method according to any one of embodiments 1b-5b, wherein said subject has hepatic steatosis.

7b. The method according to any one of embodiments 1b-6b, wherein said liver disease or disorder is selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

8b. The method according to any one of embodiments 1b-7b, wherein said liver disease or disorder is steatohepatitis.

9b. The method according to any one of embodiments 1b-8b, wherein said liver disease or disorder is liver fibrosis.

10b. The method of any one of embodiments 1b-9b, wherein said liver disease or disorder is non-alcoholic fatty liver disease (NAFLD).

11b. The method of any one of embodiments 1b-10b, wherein said liver disease or disorder is non-alcoholic steatohepatitis (NASH).

12b. The method of any one of embodiments 1b-11b, wherein said liver disease or disorder is non-alcoholic steatohepatitis (NASH), and wherein the severity of NASH is mild or moderate with a fibrosis level of F2-F3.

13b. The method of any one of embodiments 1b-12b, wherein administering a therapeutically effective amount of an ActRIIA/ActRIIB antagonist to said subject provides a decrease in liver fat fraction in said subject compared to the liver fat fraction in said subject prior to administering the therapeutically effective amount of the ActRIIA/ActRIIB antagonist.

14b. The method of any one of embodiments 1b-13b, wherein administering a therapeutically effective amount of an ActRIIA/ActRIIB antagonist to said subject provides a reduction in the degree of steatohepatitis compared to the degree of steatohepatitis present prior to administration of the ActRII antagonist.

15b. The method according to any one of embodiments 1b-14b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides relief of steatohepatitis.

16b. The method of any one of embodiments 1b-15b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides improvement in liver fibrosis.

17b. The method according to any one of embodiments 1b-16b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides for elimination of steatohepatitis and improvement in liver fibrosis.

18b. The method according to any one of embodiments 1b-17b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in the severity or a reduction in the progression of NASH.

19b. The method of any one of embodiments 1b-18b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides an improvement in liver fibrosis by at least one stage compared to the stage of liver fibrosis present prior to administration of said ActRIIA/ActRIIB antagonist.

20b. The method of any one of embodiments 1b-19b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist halts the progression of liver fibrosis to stage F3 or F4.

21b. The method of any one of embodiments 1b-20b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in the NAFLD activity score (NAS) by at least 1 point, by at least 2 points, or by at least 3 points.

22b. The method according to any one of embodiments 1b-21b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in at least one of hepatosteatosis, liver inflammation, and hepatic ballooning by at least 1 NAS point.

23b. The method of any one of embodiments 1b-22b, wherein administering a therapeutically effective amount of said ActRIIA/ActRIIB antagonist provides a reduction in at least two of steatosis, liver inflammation, and liver cell ballooning, such as hepatosteatosis and liver inflammation, or hepatosteatosis and liver cell ballooning, or liver cell ballooning and liver inflammation, by at least 1 point on the NAS scale.

24b. The method of any one of embodiments 1b-23b, wherein said subject is a subject with diabetes mellitus, a subject with obesity, or a subject with metabolic syndrome or another metabolic disorder.

25b. The method according to any one of embodiments 1b-24b, wherein said subject has type 2 diabetes mellitus.

26b. The method according to any one of embodiments 1b-25b, wherein said subject concurrently receives a standard treatment for type 2 diabetes mellitus.

27b. The method of embodiment 26b, wherein the standard treatment agent is selected from metformin, a DPP4 inhibitor, metformin/DPP4 inhibitor, sulfonylureas, thiazolidinediones, GLP-1 receptor agonists, SGLT2 inhibitors, insulin therapy.

28b. The method according to any one of embodiments 1b-27b, wherein said subject has an HbA1c level of from 6.5% to 10%.

29b. The method of any one of embodiments 1b-28b, wherein said subject is obese or overweight or has a normal BMI.

30b. The method according to any one of embodiments 1b-29b, wherein the activin type II receptor (ActRII) antagonist is an ActRIIA and/or ActRIIB antagonist.

31b. The method according to any one of embodiments 1b-30a, wherein the activin type II receptor (ActRII) antagonist is an ActRIIA and ActRIIB antagonist.

32b. The method according to any one of embodiments 1b-31b, wherein the ActRIIA/ActRIIB antagonist is an anti-ActRII antibody or a functional fragment thereof.

32b. The method of embodiment 31b, wherein said antibody or functional fragment thereof has a Kd of less than 1 nM for ActRIIA and less than 20 pM for ActRIIB.

33b. The method of embodiment 32b, wherein said ActRIIA/ActRIIB binding antibody is selected from the group consisting of:

a) an antibody comprising three CDRs under SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3;

b) an antibody comprising three CDRs under SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6;

c) an antibody comprising three CDRs under SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and three CDRs under SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6;

d) an ActRIIA/ActRIIB binding antibody comprising an HC domain having SEQ ID NO:8;

e) an ActRIIA/ActRIIB binding antibody comprising an LC domain having SEQ ID NO:7;

f) An ActRIIA/ActRIIB binding antibody comprising an HC domain comprising SEQ ID NO:8 and an LC domain comprising SEQ ID NO:7,

g) an ActRIIA/ActRIIB binding antibody comprising a VL domain comprising SEQ ID NO:9,

h) an ActRIIA/ActRIIB binding antibody comprising a VH domain comprising SEQ ID NO:10,

i) An ActRIIA/ActRIIB binding antibody comprising a VL domain comprising SEQ ID NO:9 and a VH domain comprising SEQ ID NO:10,

j) an antibody capable of binding to each of the following epitopes in ActRIIB:

(i) WLDDFN (SEQ ID NO:11) and

(ii) CEGEQDKRLHCYASW (SEQ ID NO:15),

k) an antibody capable of binding to each of the following epitopes in ActRIIB:

(i) WLDDFN (SEQ ID NO:11),

(ii) CEGEQDKRLHCYASW (SEQ ID NO:15) and

(iii) GCWLDDFNC (SEQ ID NO:12),

j) an antibody that:

(i) is capable of binding to an epitope consisting of WLDDFN (SEQ ID NO:11), and

(ii) is capable of binding to an epitope consisting of CEGEQDKRLHCYASW (SEQ ID NO:15).

34b. An ActRIIA/ActRIIB binding antibody or functional fragment thereof according to embodiment 33a, wherein the 3 CDRs of SEQ ID NO:10 are set forth as SEQ ID NOs:1, 2, and 3, and wherein the 3 CDRs of SEQ ID NO:9 are set forth as SEQ ID NOs:4, 5, and 6.

35b. The method according to any one of embodiments 33b or 34b, wherein the 3 CDRs of SEQ ID NO:8 are set forth under SEQ ID NO:1, 2 and 3, and wherein the 3 CDRs of SEQ ID NO:7 are set forth under SEQ ID NO:4, 5 and 6.

36b. The method according to any one of embodiments 1b-35b, wherein the ActRIIA/ActRIIB antagonist is bimagrumab.

37b. The method according to any one of embodiments 1b-36b, comprising administering bimagrumab in an amount of from about 3 mg/kg to about 10 mg/kg.

38b. The method according to any one of embodiments 1b-37b, comprising administering bimagrumab in an amount of about 3 mg/kg.

39b. The method according to any one of embodiments 1b-38b, comprising administering bimagrumab in an amount of about 4 mg/kg.

40b. The method according to any one of embodiments 1b-39b, comprising administering bimagrumab in an amount of about 5 mg/kg.

41b. The method according to any one of embodiments 1b-40b, comprising administering bimagrumab in an amount of about 6 mg/kg.

42b. The method according to any one of embodiments 1b-41b, comprising administering bimagrumab in an amount of about 7 mg/kg.

43b. The method according to any one of embodiments 1b-42b, comprising administering bimagrumab in an amount of about 8 mg/kg.

44b. The method according to any one of embodiments 1b-43b, comprising administering bimagrumab in an amount of about 9 mg/kg.

45b. The method according to any one of embodiments 1b-44b, comprising administering bimagrumab in an amount of about 10 mg/kg.

46b. The method according to any one of embodiments 1b-45b, wherein bimagrumab is administered every 4 weeks.

47b. The method of any one of embodiments 1b-46b, wherein bimagrumab is administered every 4 weeks for at least 3 months, at least 6 months, at least 9 months, or at least 12 months.

48b. The method according to any one of embodiments 1b-47b, comprising administering at least one additional therapeutic agent.

49b. The method of embodiment 48b, comprising administering an ActRIIA/ActRIIB antagonist in combination with at least one additional therapeutic agent for treating or preventing liver disease.

50b. The method of embodiment 49b, wherein the at least one additional therapeutic agent is an FXR agonist (e.g., tropifexor, nidufexor, obeticholic acid (6α-ethylchenodeoxycholic acid), cilofexor (GS-9674, Px-102), TERN-101 (LY2562175), EYP001 (PXL007), EDP-305, AKN-083 (Allergan), INT-787 (Intercept), INT-767 (Intercept), AGN-242256 (Allergan), MET409 (Metacrine), a steroyl-CoA desaturase-1 (SCD-1) inhibitor (e.g., arachidyl amidocholanic acid (Aramchol™)), a THR-β agonist (e.g., MGL-3196 (resmetirom), VK-2809, MGL-3745 (Madrigal)), galectin-2 inhibitor (eg, GR-MD-02/belapectin), PPAR agonist (eg, saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, IVA337 (Inventiva), CER-002 (Cerenis)), GLP-1 agonist (eg, exenatide, liraglutide, semaglutide, NC-101 (Naia Metabolic), G-49 (Astrazeneca), ZP2929 (BI/Zealand), PB-718 (Peg Bio), FGF agonist (eg, pegbelfermin (ARX618), BMS-986171, NGM-282, NGM-313, YH25724, tirzepatide, pyruvate synthase inhibitors (eg, nitazoxanide), apoptotic signal-regulated kinase 1 (ASK1) inhibitors (eg, selonsertib (GS-4997), GS-444217), acetyl-CoA carboxylase (ACC) inhibitors (eg, firsocostat (GS-0976), PF-05221304, gemcaben (Gemphire)), FXR agonist (M480 (Metacrine), NTX-023-1 (Ardelyx), INV-33 (Innovimmune)), a CCR inhibitor (eg, AD-114 (AdAlta), bertilimumab (Immune), CM-101 (ChemomAb), CCX-872 (ChemoCentryx), cenicriviroc), a thiazolidinedione (eg, MSDC-0602K, pioglitazone), a sodium-glucose cotransporter 2/1 (SGLT1/2) inhibitor (eg, remogliflozin, luseogliflozin, dapagliflozin), a DPP-4 inhibitor (sitagliptin, saxagliptin, vildagliptin, linagliptin, evogliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, gosogliptin, dutogliptin), or any combination thereof.

Implementation options (c)

1c. A pharmaceutical composition comprising an ActRIIA/ActRIIB antagonist, preferably bimagrumab, and at least one pharmaceutically acceptable excipient, for use in the treatment or prevention of a liver disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an ActRIIA/ActRIIB antagonist, preferably bimagrumab.

2c. A pharmaceutical composition comprising an ActRIIA/ActRIIB antagonist, preferably bimagrumab, for use according to any one of embodiments 1a-50a and at least one pharmaceutically acceptable excipient.

Implementation options (d)

1d. Use of an ActRIIA/ActRIIB antagonist as defined in any one of embodiments 1a-50a for the manufacture of a medicament for the treatment of a liver disease or disorder.

2d. Use of an ActRIIA/ActRIIB antagonist as defined in any one of embodiments 1a-50a for the manufacture of a medicament for preventing a liver disease or disorder.

3d. Use of bimagrumab in the manufacture of a medicinal product for the treatment or prevention of liver disease or disorder.

4d. Use of bimagrumab according to embodiment 3d, wherein said liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or liver fibrosis.

5d. Use of bimagrumab according to embodiment 4d, wherein the liver disease or disorder is NASH.

Implementation options (e)

1e. Use of a pharmaceutical composition comprising an ActRIIA/ActRIIB antagonist of any one of embodiments 1a-50a and at least one pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment or prevention of a liver disease or disorder.

[105] An ActRIIA/ActRIIB antagonist, such as bimagrumab, method, pharmaceutical composition, or use according to any of the above embodiments, wherein the NAFLD is characterized by a NAFLD activity score (NAS) greater than or equal to 1, greater than or equal to 2, greater than or equal to 3, or greater than or equal to 4.

[106] An ActRIIA/ActRIIB antagonist, method, pharmaceutical composition, or use according to any of the above embodiments, wherein NASH is confirmed based on a liver biopsy (also referred to as biopsy-confirmed NASH), and the severity of NASH is mild or moderate with a fibrosis level of F2-F3.

[107] An ActRIIA/ActRIIB antagonist, method, pharmaceutical composition, or use according to any of the above embodiments, wherein the presence of NASH has been demonstrated by:

i) histological confirmation of NASH based on a liver biopsy obtained 2 years or less prior to initiation of treatment with an ActRIIA/ActRIIB agonist according to any of the above embodiments, with a diagnosis consistent with NASH, a fibrosis level of F1, F2, F3, or F4, no diagnosed alternative chronic liver diseases, or

ii) phenotypic diagnosis of NASH, or

iii) non-invasive, disease-specific biomarkers.

[108] An ActRIIA/ActRIIB antagonist, such as bimagrumab, the method, pharmaceutical composition, or use of any of the above embodiments, wherein the liver disease is associated with unbalanced lipid metabolism in the liver and/or increased levels of body fat.

[109] In any of the above-described embodiments, liver fat levels are assessed by magnetic resonance imaging (MRI), more specifically by determining the proton density fraction of fat by magnetic resonance imaging (MRI-PDFF).

[110] In any of the embodiments described herein, administration of a therapeutically acceptable amount of an ActRIIA/ActRIIB antagonist, such as bimagrumab, results in a decrease in liver fat fraction in the patient. For example, in any of the above embodiments, treatment with an ActRII antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and more preferably an anti-ActRII receptor antibody, most preferably bimagrumab, results in a decrease in liver fat fraction in the patient compared to the liver fat fraction present in the patient prior to treatment, optionally wherein the liver fat fraction is assessed by magnetic resonance imaging proton density function (MRI-PDFF).

[111] In any of the above embodiments, treatment with an ActRII antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and more preferably an anti-ActRII receptor antibody, most preferably bimagrumab, results in a decrease in liver fat fraction in the patient of 40% or greater (e.g., 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 65%, 70%, 75% or greater) compared to the liver fat fraction present in the patient prior to treatment, optionally wherein the liver fat fraction is assessed by MRI-PDFF. In any of the above embodiments, the patient's liver fat fraction is reduced by at least 2 (e.g., at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12) percentage points following administration to the patient of an ActRII antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and more preferably an ActRII receptor antibody, most preferably bimagrumab, compared to the patient's liver fat fraction before treatment, optionally assessing the liver fat fraction using MRI-PDFF.

[112] In some aspects, an ActRIIA/ActRIIB antagonist as defined herein is for the treatment of a liver disease or disorder, e.g., a chronic liver disease or disorder, e.g., a disease or disorder selected from the group consisting of cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis of pregnancy, parenteral nutrition-associated cholestasis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), steatohepatitis, drug-induced bile duct injury, gallstones, liver cirrhosis, alcoholic cirrhosis, cystic fibrosis (CFLD), bile duct obstruction, cholelithiasis, liver fibrosis, dyslipidemia, portal hypertension, metabolic syndrome, hypercholesterolemia, progressive liver fibrosis due to any of the above and/or infectious hepatitis, such as the liver disease or disorder NAFLD, NASH, liver fibrosis, hepatosteatitis, or liver steatosis.

[113] In another aspect, the pharmaceutical composition is provided as a unit dosage form comprising bimagrumab in an amount of from about 100 to about 200 mg/mL, preferably bimagrumab in an amount of about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 mg/mL bimagrumab. Such unit dosage form compositions may be provided in a suitable form for intravenous administration. Such unit dosage form compositions may be provided in a suitable form for subcutaneous administration. Also, such compositions in the form of a standard dosage form are intended for use in the treatment of chronic liver disease, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile duct injury, cholelithiasis, liver cirrhosis, alcoholic cirrhosis, cystic fibrosis, bile duct obstruction, cholelithiasis, liver fibrosis, for example, for use in the treatment of non-alcoholic steatohepatitis (NASH), for example, for use in the treatment of phenotypic non-alcoholic steatohepatitis (NASH).

[114] In another aspect, an ActRIIA/ActRIIB antagonist as defined herein is for preventing or delaying the progression of a chronic liver disease or disorder to a later stage or more serious condition, such as preventing or delaying the progression of a chronic liver disease or disorder selected from the group consisting of NAFLD, NASH, and liver fibrosis.

Subjects

[115] According to the present disclosure, subjects receiving an ActRIIA/ActRIIB antagonist as described herein may suffer from or be at risk of having a liver disease or disorder, such as those defined above.

[116] In some embodiments, the subject with the liver disease or disorder is obese, overweight, or has a normal BMI. In one embodiment, the subject with the liver disease or disorder has a body mass index (BMI) of 25 kg/m ² or greater. In another embodiment, the subject with the liver disease or disorder has a BMI of 26 kg/m ² or greater. In another embodiment, the subject with the liver disease or disorder has a BMI of 27 kg/m ² or greater. In another embodiment, the subject with the liver disease or disorder has a BMI of 28 kg/m ² or greater. In another embodiment, the subject with the liver disease or disorder has a BMI of 29 kg/m ² or greater. In one embodiment, the subject with the liver disease or disorder is obese. In another embodiment, the subject with the liver disease or disorder has a BMI of 30 kg/m ² or greater. In one embodiment, the subject with the liver disease or disorder is overweight. In another embodiment, the subject with liver disease or disorder has a BMI ≥ 25 and < 30 kg/ ^m2 . In one embodiment, the subject with liver disease or disorder has a normal BMI. In another embodiment, the subject with liver disease or disorder has a BMI less than 25 kg/ ^m2 .

[117] In one embodiment, the subject with the liver disease or disorder has hypertension and/or hypertriglyceridemia and/or low high-density lipoprotein (HDL) levels.

[118] In one embodiment, the subject with the liver disease or disorder has type 2 diabetes mellitus and a BMI ≥ 30 kg/ ^m2 and at least one of hypertension, hypertriglyceridemia, and low HDL.

Combination therapy

[119] In practicing certain methods of treatment or routes of use of the present disclosure, a therapeutically effective amount of an ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist (e.g., an antibody to an ActRII receptor or an antigen-binding fragment thereof, such as bimagrumab) is administered to a patient, such as a mammal (e.g., a human). While it is understood that the disclosed methods are provided for treating patients with a liver disease or disorder using an ActRII antagonist (e.g., bimagrumab), this does not preclude that if the patient is ultimately treated with an ActRII antagonist, such ActRII antagonist therapy would necessarily be monotherapy. Indeed, if a patient is selected for treatment with an ActRII antagonist, the ActRII antagonist (e.g., bimagrumab) can be administered according to the methods or routes of administration of the present disclosure either alone or in combination with other agents and therapies for treating a liver disease or disorder in patients, such as in combination with at least one additional therapeutic agent. When co-administered with one or more additional therapeutic agents, the ActRII antagonist (e.g., bimagrumab) can be administered either simultaneously with the other agent, alone, or sequentially. When administered sequentially, the treating physician will decide on the appropriate sequence of administration of the ActRII antagonist (e.g., bimagrumab) in combination with the other agents and the appropriate dosages for co-delivery. Accordingly, in one aspect of the present invention there is also provided a pharmaceutical combination comprising (a) an ActRII antagonist, preferably an ActRIIA and/or ActRIIB antagonist, and more preferably an anti-ActRII receptor antibody, most preferably bimagrumab, and (b) at least one additional therapeutic agent.

[120] In the treatment or prevention of liver disease or disorder in a subject in need thereof, various therapies may be successfully combined with an identified ActRII antagonist (eg, bimagrumab). The at least one additional therapeutic agent can be an FXR agonist, a steroyl-CoA desaturase-1 (SCD-1) inhibitor (e.g., arachidyl amidocholanic acid (AramcholTM)), a THR-β agonist (e.g., MGL-3196 (Resmetirom), VK-2809, MGL-3745 (Madrigal)), a galectin-2 inhibitor (e.g., GR-MD-02/belapectin), a PPAR agonist (e.g., saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, IVA337 (Inventiva), CER-002 (Cerenis), a GLP-1 agonist (e.g., exenatide, liraglutide, semaglutide, NC-101 (Naia Metabolic), G-49 (Astrazeneca), ZP2929 (BI/Zealand), PB-718 (Peg Bio), FGF agonist (e.g., pegbelfermin (ARX618), BMS-986171, NGM-282, NGM-313, YH25724, tirzepatide, pyruvate synthase inhibitors (e.g., nitazoxanide), apoptotic signal-regulated kinase 1 (ASK1) inhibitor (e.g., selonsertib (GS-4997), GS-444217), acetyl-CoA carboxylase (ACC) inhibitor (e.g., firsocostat (GS-0976), PF-05221304, gemcaben (Gemphire)), FXR agonist (M480 (Metacrine), NTX-023-1 (Ardelyx), INV-33 (Innovimmune)), a CCR inhibitor (eg, AD-114 (AdAlta), bertilimumab (Immune), CM-101 (ChemomAb), CCX-872 (ChemoCentryx), cenicriviroc), a thiazolidinedione (eg, MSDC-0602K, pioglitazone), a sodium glucose cotransporter-2 and 1 (SGLT1/2) inhibitor (eg, remogliflozin, luseogliflozin, dapagliflozin), a DPP-4 inhibitor (sitagliptin, saxagliptin, vildagliptin, linagliptin, evogliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, gosogliptin, dutogliptin), or any combination thereof.

[121] As used herein, the term "FXR agonist"/"FXR agonists" refers to any agent that is capable of binding to and activating the farnesoid X receptor (FXR), which may be referred to as the bile acid receptor (BAR) or the NR1H4 receptor (nuclear receptor subfamily 1, group H, member 4). An FXR agonist may act as an FXR agonist or a partial agonist. The agent may be, for example, a small molecule, an antibody, or a protein, preferably a small molecule. FXR agonist activity may be measured in several different ways, such as in an in vitro assay using a cell-free fluorescence resonance energy transfer (FRET) assay as described in Pellicciari, et al. Journal of Medicinal Chemistry, 2002, vol. 15, no. 45:3569-72.

[122] The FXR agonist used herein refers, for example, to the compounds disclosed in: WO 2016/096116, WO 2016/127924, WO 2017/218337, WO 2018/024224, WO 2018/075207, WO 2018/133730, WO 2018/190643, WO 2018/214959, WO 2016/096115, WO 2017/118294, WO 2017/218397, WO 2018/059314, WO 2018/085148, WO 2019/007418, CN 109053751, CN 104513213, WO 2017/128896, WO 2017/189652, WO2017/189663, WO 2017/189651, WO 2017/201150, WO 2017/201152, WO 2017/201155, WO2018/067704, WO 2018/081285, WO 2018/039384, WO 2015/138986, WO 2017/078928, WO2016/081918, WO 2016/103037, WO 2017/143134.

[123] The FXR agonist is preferably selected from the following: tropifexor, nidufexor, obeticholic acid (6α-ethylchenodeoxycholic acid), cilofexor (GS-9674, Px-102),

Pharmaceutical compositions

[124] An ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist, such as an anti-ActRII receptor antibody or antigen-binding fragment thereof, such as bimagrumab, can be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. In addition to the ActRII antagonist, such a composition can contain carriers, various diluents, excipients, salts, buffers, stabilizers, solubilizers and other materials known in the art. The characteristics of the carrier will depend on the route of administration. The pharmaceutical compositions for use in the disclosed methods can also contain at least one or more additional therapeutic agents for treating a particular target disorder. For example, the pharmaceutical composition can also include antidiabetic agents or weight loss agents, or agents useful for treating metabolic disorders, or agents that can be used to treat or prevent a liver disease or disorder. Such additional factors and/or agents may be included in the pharmaceutical composition to provide a synergistic effect with ActRII binding molecules or to minimize side effects caused by ActRII antagonists, such as an ActRIIA and/or ActRIIB antagonist (e.g., an ActRII receptor antibody or antigen-binding fragment thereof, such as bimagrumab). In preferred embodiments, pharmaceutical compositions for use in the disclosed methods comprise bimagrumab at 150 mg/mL.

[125] The pharmaceutical compositions disclosed herein can be prepared in a conventional manner. In one embodiment, the pharmaceutical composition is provided in lyophilized form. For immediate administration, it is dissolved in a suitable aqueous vehicle, such as sterile water for injection or sterile buffered saline. If it is considered desirable to provide a larger volume solution for administration by infusion rather than as a bolus injection, it may be advantageous to include human serum albumin or the patient's own heparinized blood in the saline solution during formulation. The presence of an excess of such physiologically inert protein prevents loss of antibodies due to adsorption to the walls of the container and tubing system used with the infusion solution. If albumin is used, a suitable concentration is from 0.5 to 4.5% by weight of the saline solution.

[126] In some embodiments of the disclosed methods and routes of use, an ActRII antagonist, such as an anti-ActRII antibody, such as bimagrumab, is formulated as a lyophilisate. In the event that a therapeutically effective amount of an ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist (e.g., an anti-ActRII receptor antibody or antigen-binding fragment thereof, such as bimagrumab) is administered, the ActRII antagonist will be provided as a non-pyrogenic, parenterally acceptable solution. The pharmaceutical composition for intravenous or subcutaneous administration may comprise, in addition to the ActRII antagonist, an isotonic carrier medium such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other carrier medium as known in the art. The pharmaceutical composition of the present disclosure can be formulated to be compatible with the intended route of administration (e.g., oral compositions typically include an inert diluent or an edible carrier). Other non-limiting examples of routes of administration include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Pharmaceutical compositions compatible with each intended route are well known in the art.

Dosage regimen and routes of administration

[127] Dosage regimens are adjusted to provide the optimum desired response (e.g., therapeutic response). For example, a single bolus dose may be administered, several divided doses may be administered over a period of time, or the dose may be proportionally decreased or increased as the needs of the therapeutic situation dictate. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. The parameters of the dosage unit forms of the present invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved and the limitations of the art with respect to formulating such active compound for the treatment of sensitivity in individuals.

[128] Depending on the compound used, the target disease or disorder, and the stage of such disease or disorder, the dosing regimen, i.e., the dose and/or frequency of administration of a pharmaceutical composition comprising an ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist (e.g., an anti-ActRII receptor antibody or antigen-binding fragment thereof, such as bimagrumab), may vary. Depending on the compound used, the target disease or disorder, and the stage of such disease or disorder, the dosing regimen, i.e., the dose and/or frequency of administration of a pharmaceutical combination comprising a) an ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist (e.g., an anti-ActRII receptor antibody or antigen-binding fragment thereof, such as bimagrumab), and b) at least one additional therapeutic agent, may vary.

[129] For administration of a composition comprising an antibody in methods for treating a liver disease or liver disorder, or for use in treating or preventing a liver disease or liver disorder, the dose of the antibody is in the range of about 0.0001 to about 100 mg/kg, and more typically about 0.01 to about 30 mg/kg of body weight of the subject. For example, doses are about 3 mg/kg body weight, about 5 mg/kg body weight, or about 10 mg/kg body weight in the range of about 3 to about 10 mg/kg, such as about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10 mg/kg body weight. Doses are repeated as needed and can range from about once a week to about once every 10 weeks, such as once every 4 weeks or once every 8 weeks.

Sets

[130] The present disclosure also encompasses kits for use in methods of treating or preventing a liver disease or disorder that can comprise an ActRII antagonist, such as an ActRIIA and/or ActRIIB antagonist (e.g., an anti-ActRII receptor antibody or antigen-binding fragment thereof, such as bimagrumab), such as in liquid or lyophilized form, or a pharmaceutical composition comprising such an ActRII antagonist, such as bimagrumab. Additionally, such kits can comprise devices for administering the ActRII antagonist (e.g., a syringe and vial, a prefilled syringe, a prefilled pen) and instructions for use. Such kits can comprise additional therapeutic agents (described above), such as for delivery in combination with the encapsulated ActRII antagonist, such as bimagrumab.

[131] The phrase "administration device" is used to define any accessible instrument for systemic administration of a drug to a patient, including, but not limited to, a pre-filled syringe, vial and syringe, pen, auto-injector, IV drip and bag, pump, etc. With such items, the patient may self-administer the drug (i.e., administer the drug to himself) or the drug may be administered by a physician.

[132] Each component of the kit is usually placed in a separate container, and all the different containers are in one package along with instructions for use.

[133] It should be understood that each embodiment may be combined with one or more other embodiments to the extent that such combination is consistent with the description of the embodiments. Furthermore, it should be understood that the embodiments presented above are intended to include all embodiments, including such embodiments resulting from combinations of embodiments.

[134] Other features, objects and advantages of the present disclosure will be apparent from the description and drawings, as well as from the claims.

EXAMPLES

[135] The following examples illustrate the present disclosure described above, but are not intended to limit the scope of the present disclosure in any way. Other variations of the present disclosure will be readily apparent to one of ordinary skill in the art and are encompassed by the appended claims.

Examples 1 and 2. Preclinical study

[136] High activin A expression was observed in patients with NAFLD, and high activin A levels were significantly associated with the degree of liver fibrosis in patients with NASH (Yndestad et al. , Am J Gastroenterol. 2009 Sep;104(9):2196-205). Several mouse models are available to study liver fibrosis, including the high-fat diet-induced obesity NASH model, a long-term (20 week) disease-relevant NASH model that can be used to study the effects of treatment on NASH fibrosis in a therapeutic treatment regimen, and the CCl ₄ -induced liver fibrosis model, a short-term (4 week) chemically induced model that can be used to study the effects of treatment on fibrosis in a disease prevention regimen.

Example 1. DAX19 in vivo 1 - NASH model of HF/NASH diet-induced obesity

[137] Adult male C57BL/6J mice were housed with unlimited access to water and food. ad libitum. Mice were fed a HF/NASH diet (40 kcal% fat, 2% cholesterol, 40 kcal% carbohydrate, Research Diets, D09100301 or SSniff Special Diets, with fructose-sucrose solution (42 g/L, 55% fructose and 45% sucrose by weight) added to the drinking water). Age-matched animals were maintained on a standard diet (Normal Diet, ND, Kliba Nafag, 3892) and were given tap water. Mice were fed the HF/NASH diet for 20 weeks. At week 8 of HF/NASH feeding, HF/NASH-treated animals were randomized to treated or untreated groups according to body weight, total lean and fat mass, and liver fat content measured by MRI. The study included three groups of mice. Group 1: normal diet/water (n=7); Group 2: HF/NASH+control antibody (SB-18-SN99, 30 mg/kg) subcutaneously q7d (n=9); and Group 3: HF/NASH+CDD866 30 mg/kg, subcutaneously, q7d (n=9). CDD866 is a chimeric murinized version of BYM338 (bimagrumab) in which the human Fc region of the antibody is replaced with a murine Fc. Body weight was measured weekly, and fat and lean mass were measured at 0, 4, 7, 14, and 20 weeks of HF/NASH feeding using a mouse body composition analyzer with nuclear magnetic resonance (NMR), and liver fat was assessed at 8, 12, 16, and 20 weeks of HF/NASH feeding using magnetic resonance imaging (MRI).

[138] As shown in Figure 1, CDD866 treatment increased body weight (Figure 1A) and lean mass (Figure 1B). Total fat mass was decreased at 14 weeks of HF/NASH feeding (Figure 1C). Liver fat % was decreased at all time points measured, including a 20% and 24% decrease at 12 and 20 weeks of HF/NASH feeding, respectively (Figure 1D).

[139] PicroSirius Red staining of liver sections at week 20 showed that CDD866 treatment significantly reduced liver fibrosis by 30% compared to control treatment (Figure 2A and 2B). Histopathological semiquantitative assessment of PicroSirius-red stained liver sections did not reveal statistically significant changes, although a trend toward reduced fibrosis was observed in CDD866-treated liver samples (Figure 2C).

[140] CDD866 treatment also resulted in a decrease in myofibroblast marker a-SMA positive staining in the liver (-30% compared to the control group) (Figure 2D), and the number of IBA1-positive liver crown-like structures was significantly reduced in CDD866-treated liver samples (Figure 2E).

[141] Histopathological semiquantitative evaluation of hematoxylin and eosin stained liver sections revealed a significant reduction in the severity of micro- and macrovesicular hepatic steatosis with CDD866 treatment (Figure 2F).

[142] This observation was further supported by a decrease in gene expression of liver fibrosis markers (Figure 3A) and liver inflammation markers F4/80 and TNFα (Figure 3B). A decrease in serum TIMP1 (Figure 3C) and PIIINP (Figure 3D) was also observed after 6 weeks of treatment (-36%/-19% compared to control), which remained stable over time (-38%/-24%, end of study).

[143] In blood analysis, a decrease in serum AST (-27%) and GGT (-62%) levels was observed at 20 weeks of HF/NASH feeding (Figure 4).

Example 2. DAX19 in vivo 2 - model of CCl ₄ -induced liver fibrosis

[144] Eight-week-old male C57BL/6J mice were maintained in a temperature- and humidity-controlled environment with a 12-hour light/12-hour dark cycle and free access to standard rodent chow (Kliba-Nafag, Kaiseraugst, Switzerland) and tap water. To induce fibrosis, mice were treated with CCl4 for 4 weeks 3 times per week intraperitoneally (i.p.). Animals were randomized into three groups of mice. Group 1) control: olive oil, i.p., 5 ml/kg 3 times/week (n=12), group 2) CCl4, i.p., 5 ml/kg, 15% CCl4, 3 times/week+control antibody s.c., q7d (n=12) and group 3) CCl4, i.p., 5 ml/kg, 15% CCl4, 3 times/week+CDD866 30 mg/kg, s.c., q7d (n=10). Body weight was measured three times a week and fat and lean mass were measured at 0, 2 and 4 weeks using a mouse body composition analyzer with nuclear magnetic resonance (NMR) (Minispec LF50; Bruker Optics, Germany).

[145] As shown in Figure 5, CDD866 treatment resulted in an increase in body weight (Figure 5A) and lean mass (Figure 5B). A decrease in total fat mass was also observed at days 14 and 28 (Figure 5C). This decrease in total fat mass was accompanied by a decrease in epididymal white adipose tissue (WAT) (Figure 5D) and an increase in brown adipose tissue (BAT) at day 28 (Figure 5E).

[146] PicroSirius Red staining of liver sections at week 4 showed that CDD866 treatment significantly reduced liver fibrosis by 11% compared to control treatment (ND) (Figures 6A and 6B). A significant reduction in anti-smooth muscle antibody (aSMA) levels was also observed in the liver of CDD866-treated mice (-16% compared to Veh) (Figures 6C and 6D). CDD866-treated animals showed a significant increase in fibrosis biomarkers, TIMP-1 and PIIINP, in serum (Figure 6E).

[147] These observations were further confirmed by gene expression levels: at week 4, a decrease of approximately 30-40% was observed for Col1a1 , Col3a1 and Mmp-2 , while an increase was observed for Timp-1 (Figure 7).

Conclusion

[148] Using the ActRII antagonist CDD866 (murinized BYM338) in two different models, it can be shown that liver fibrosis is significantly reduced by administration of the ActRII antagonist.

Example 3. Clinical study

Research plan

[149] BYM338X2211 was a non-confirmatory, randomized, investigator- and subject-blinded, placebo-controlled, parallel-group study investigating a 48-week treatment period with intravenous bimagrumab in overweight/obese patients with type 2 diabetes. The study was registered under the ClinicalTrials.gov identifier NCT03005288. Seventy-five patients were enrolled and randomized. Liver, visceral, and subcutaneous fat were assessed in patients who consented to optional MRI.

Key inclusion criteria

Men and women, aged 18 to 75 years (inclusive), in stable health based on history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.

Type 2 diabetes mellitus (T2D) with HbA1c level from 6.5% to 10% (inclusive) at screening, with or without background therapy for T2D and metformin and/or DPP4 inhibitor, and stable treatment for approximately 3 months prior to randomisation.

Body mass index (BMI) from 28 to 40 kg/ ^m2 (inclusive) at screening.

Body weight from 65 to 140 kg (inclusive) at the time of screening and stable body weight (±5 kg) according to the anamnesis (patient report) and stable physical activity for 3 months before screening.

During screening, the main vital signs should be as follows: body temperature when measured in the oral cavity 35.0-37.5°C, systolic blood pressure 90-150 mmHg, diastolic blood pressure 50-90 mmHg, pulse rate 50-100 beats/min.

Key exclusion criteria

Pregnant or breastfeeding (lactating) women, where pregnancy is defined as the condition of a woman after conception and continuing until the end of the gestational period, confirmed by a positive laboratory test for hCG.

Women of childbearing potential were defined as all women physiologically capable of becoming pregnant if they were not using highly effective contraception during dosing and for 6 months after discontinuing study drug.

Diabetes mellitus other than type 2, such as type 1 diabetes mellitus, surgically induced diabetes mellitus; “labile” type 2 diabetes mellitus according to the investigator; history of severe hypoglycemia episodes in the year preceding screening; or hypoglycemia unawareness.

Abnormal liver function test results such as AST, ALT, alkaline phosphatase, or serum bilirubin levels, or abnormal lipase and/or amylase levels.

History of clinically significant arrhythmia, unstable angina, myocardial infarction or stroke, coronary artery bypass grafting or percutaneous coronary intervention (eg, angioplasty or stent placement) within 6 months of screening or 1 year for drug-eluting stents.

Use of any anti-obesity medications, dietary supplements, or over-the-counter weight-loss products within 3 months prior to screening. Use of medications known to cause weight gain, such as certain anticonvulsants and psychotropic medications (eg, clozapine), within 3 months prior to screening.

Screening (days -21 to -8)

[150] To determine eligibility for participation in the study, participants completed a screening visit at the study center. Subjects who were screened as eligible for inclusion were assigned to baseline assessment procedures.

[151] Lifestyle interventions included dietary advice for weight loss with a daily caloric deficit of 500 kcal, with a diet consistent with American Diabetes Association (ADA) guidelines for optimal glycemic control, and a protein intake of at least 1.2 g/kg/day to support muscle anabolism and offset the caloric deficit. Patients were counseled on physical activity and encouraged to follow established guidelines (American Diabetes Association, Starter Walking Plan, adapted from I Hate to Exercise , ^2nd edition, Charlotte Hayes). These interventions were initiated at screening after eligibility was confirmed. Antiobesity trials are designed to demonstrate treatment benefits on weight/composition over first-line therapy with lifestyle modifications. A daily caloric deficit of 500 kcal is the standard approach and is expected to result in weight loss over the treatment period. The American Diabetes Association (ADA) walking program is tailored to the population in this study and is a gentle, easy-to-implement approach to physical activity. Exercise is known to enhance the effects of bimagrumab on muscle function, maintaining the effectiveness of bimagrumab treatment on body composition and weight.

Baseline (days -7 to -1)

[152] Prior to dosing (Day 1), patients who met study inclusion criteria after screening returned to the clinic for baseline assessments.

[153] Baseline scans were performed before the active drug or placebo dose on day 1 and included determination of liver fat, abdominal subcutaneous fat, and abdominal visceral fat using magnetic resonance imaging (MRI) and body composition using dual-energy X-ray absorptiometry (DXA). Additional patient assessments at baseline included anthropometric measurements (height, weight, waist circumference, hip circumference, waist-to-hip ratio, and body mass index (BMI) (body weight (kg)/[height (m)] ² ). Other baseline measurements included fasting glucose and insulin levels and HbA1c levels.

Randomization and dosing (day 1)

[154] Patients who met inclusion criteria based on screening and baseline assessments were randomized in a 1:1 ratio to receive either bimagrumab or placebo. Randomization was stratified according to baseline BMI into 2 groups:

BMI from 28 kg/ ^m2 to 33 kg/ ^m2 (inclusive) and

BMI from 33 kg/ ^m2 to 40 kg/ ^m2 (inclusive).

[155] Patients were assigned to one of the following 2 treatment groups in a 1:1 ratio

BYM338 (bimagrumab) 10 mg/kg up to a maximum of 1200 mg monthly (12 doses)

Placebo monthly (12 doses)

[156] Bimagrumab or placebo was administered via intravenous infusion over 30 minutes, followed by an observation period that included sampling to assess safety and tolerability, as well as PK.

Treatment period (days 1-336)

[157] Patients continued to receive background standard treatment to avoid deterioration of glycemic control in accordance with the eligibility criteria (see main eligibility criteria above) throughout the study, allowing for the assessment of the additional benefit of bimagrumab treatment on glycemic parameters. T2D treatment was restricted to specific therapies to ensure homogeneity of the study population and to allow data interpretation. Oral diabetes therapy with metformin and/or a DPP4 inhibitor facilitated the selection of patients in the early stages of the disease and therefore without significant comorbidities. Furthermore, these drugs were less likely to affect body weight and thus less likely to confound study results. If glycemic control improved during the study, reductions in antidiabetic treatment were allowed to prevent hypoglycemia.

[158] Bimagrumab or placebo was administered by intravenous infusion over 30 minutes followed by an observation period once every 4 weeks for a total of twelve doses. Bimagrumab was dosed based on body weight at 10 mg/kg with a maximum dose of 1200 mg for body weights equal to or greater than 120 kg. Placebo was given as D5W, 5% dextrose.

[159] Patients received regular monitoring and advice on diet and physical activity as part of their monthly visits to the study center throughout the study.

[160] Patients were invited to return to the study center for dosing approximately every 4 weeks during the treatment period. During these visits, patients were assessed for safety, tolerability, PK, and efficacy.

[161] The treatment period ended 4 weeks after the last administration (on day 308/week 44).

Follow-up (days 364-392)

[162] After completion of the treatment period, patients entered a follow-up period of 8 weeks with regular monitoring of safety and efficacy (at week 52) until the end-of-study visit (EOS) at week 56, 12 weeks after the last administration of study drug.

Dose justification

[163] In healthy volunteers (HV) and patients with sIBM, a 10 mg/kg dose of bimagrumab has been shown to produce exposure levels (i.e., greater than 10 μg/mL) at which anabolic effects are observed and maintained over dosing intervals of 4 weeks [CBYM338X2102 (N=6 subjects), CBYM338X2104 (N=47 subjects)], up to six doses [CBYM338X2109 (N=35 subjects)], and up to one year [CBYM338B2203 (N=54 patients with sIBM)]. The minimum target exposure threshold for bimagrumab is approximately 10 μg/mL, the concentration below which nonlinear clearance is observed, suggesting loss of full receptor saturation and target-mediated drug distribution. In clinical studies to date, bimagrumab concentrations of approximately 10 mcg/mL or greater for at least 4 weeks in HV and greater than one year in sIBM patients were safe, well tolerated, and demonstrated to produce increases in thigh muscle volume. A 26-week toxicology study in cynomolgus monkeys showed chronic exposure at the NOAEL (300 mg/kg/week) to be approximately 300- and 55-fold higher for AUC and Cmax, respectively, compared to human exposure at 10 mg/kg at steady state.

[164] Dosing in this study was based on body weight for patients weighing up to 120 kg and was capped at 1200 mg for patients weighing between 120 and 140 kg. Body weight-based dosing has been shown to reduce intersubject/patient variability in exposure and was used on an as-needed basis. The capped dose was chosen for body weight > 120 kg due to uncertainty about the impact of high body weight and body composition (% fat mass vs. % lean mass) on the pharmacokinetics, exposure, and safety profile of bimagrumab. To date, pharmacokinetic data are limited in obese subjects, with the maximum body weight of dosing subjects being 116 kg in studies conducted with bimagrumab in overweight obese subjects with insulin resistance (N=10) and healthy obese subjects (N=6). The maximum amount of bimagrumab administered to date is 3500 mg (at 30 mg/kg) i.v. and as a single dose to a maximum body weight of 116 kg. This dose did not demonstrate excessive exposure and did not raise safety concerns. A limited dose was chosen for these subjects to avoid excessive exposure and maintain bimagrumab levels within thresholds for safe anabolic effects over 4-week dosing intervals. In particular, the selected amount of 1200 mg corresponds to a body weight-based dose in the range of 10 to 8.6 mg/kg for body weights in the range of 120-140 kg, which is predicted to result in exposure levels within the safe and effective range for bimagrumab, and with minimal risk of overexposure.

Justification for the duration of treatment

[165] The treatment duration of 48 weeks was chosen based on the time profile as well as the maximal effect of bimagrumab on body fat mass. While there is typically a satiation effect in lean mass gain with bimagrumab, fat loss does not appear to stabilize over a period of 24 weeks or even up to 64 weeks.

Justification for the duration of the follow-up period

[166] An extended follow-up period of 8 weeks was chosen to monitor the durability of the bimagrumab treatment effect on body fat mass, lean mass, and glycemic control after treatment. The EOS visit, conducted 12 weeks after the last administration, covers the washout period of bimagrumab exposure associated with the anabolic effect (approximately 8 weeks).

Glucose Control Assessment

[167] Fasting glucose and insulin levels were measured at different time points.

HbA1c

[168] HbA1c reflects average glucose concentrations over the past 3 months and therefore provides a useful measure of glycemic control of bimagrumab over this time period. It is the standard endpoint used to assess the glycemic efficacy of any antidiabetic drug. HbA1c is a key glycemic parameter that correlates with a reduction in the risk of diabetic complications.

HOMA2-IR

[169] Patients had fasting insulin and glucose assessed at screening to assess the degree of insulin resistance using the homeostatic model assessment of insulin resistance (HOMA2-IR) and the inverse HOMA2-IR model.

QUICKLY

[170] QUICKI is being evaluated because it is a superior estimate of insulin resistance to HOMA2-IR in patients with diabetes and elevated fasting glucose, eg, >170 mg/dL (Yokoyama et al (2004) J. Clin. Endocrinol. Metab. p. 1481). QUICKI is a derived index of insulin sensitivity using fasting glucose and insulin levels and provides additional and complementary information to that obtained with HOMA2-IR (Hrebícek et al. (2002) J. Clin. Endocrinol. Metab., p. 144-7).

Visualization

Scanning with DXA

[171] Dual-energy X-ray absorptiometry (DXA) is used to assess changes in body composition, including total body fat and lean mass (FBM and LBM) and appendicular skeletal fat and muscle mass (aFBM and aLBM). DXA machines use an X-ray source that generates and separates two types of energy to measure bone and soft tissue mineral mass, which is used to estimate fat and fat-free mass (or lean body mass). The test is fast (~5-6 min), accurate (0.5-1%), and noninvasive. DXA scanners have the accuracy needed to detect changes in muscle mass as small as 5%.

MRI scanning

[172] Magnetic resonance imaging (MRI) is used to assess changes in liver fat percentage (% fat fraction or %FF), abdominal visceral and subcutaneous adipose tissue volumes, and paravertebral muscle cross-sectional area and associated fat content (both intermuscular adipose tissue content-IMAT and muscle FF content). All images were acquired in the axial plane using imaging pulse sequences optimized for water-fat separation and adapted to the capabilities of the MRI system.

Primary Variable Analysis

[173] The primary objective of the study was to evaluate the effect of bimagrumab on total body fat mass. The primary efficacy variable was change in fat mass from baseline to week 48.

[174] The study design allowed for assessment of efficacy based on the following dual criteria: 1) statistical significance (superior treatment effect, 1-sided level 10%) on fat mass; and 2) clinical significance of the change in fat mass (estimated mean treatment effect of 5% or greater). A 5% weight loss has been shown to result in clinical benefit in the overweight/obese and T2D population (Franz et al. (2015) J. Acad. Nutr. Diet., p. 1447–1463). Randomization was stratified by BMI categories (≥28 kg/ ^m2 and ≤33 kg/ ^m2 , from >33 kg/ ^m2 to ≤40 kg/ ^m2 ) to achieve an approximate balance in the BMI distribution between the two treatment groups. The cutoff of 33 kg/ ^m2 represents the expected mean BMI in this population.

[175] A longitudinal mixed-effects model was used with change from baseline in fat mass in kilograms as the dependent variable, treatment group, time, and time*treatment interaction as fixed effects. Baseline fat mass and baseline BMI values were included in the model as covariates. Time was modeled as a categorical variable, and unstructured within-subject covariate was used. Data from both randomization groups (BMI category at randomization) were included in the model. This model estimated change from baseline (absolute and %) in fat mass in kg at week 48. As a secondary analysis, the proportion of patients achieving at least 5% fat loss at weeks 24 and 48 was presented by treatment group.

Secondary Variable Analysis

[176] The secondary efficacy variable is the change in HbA1c at 24 and 48 weeks. Other parameters of glucose control and insulin sensitivity (fasting glucose and insulin, HOMA2-IR, QUICKI, Matsuda index) and body anthropometric measurements (body weight, BMI, waist circumference, waist-to-hip ratio, and lean body mass (LBM) measured by DXA) are other secondary efficacy variables. Body fat mass measured by DXA at 24 weeks was also a secondary efficacy variable.

[177] The secondary variable HbA1c was analyzed similarly to fat mass to assess the statistical significance (superior treatment effect, 1-sided level 10%) of bimagrumab treatment on HbA1c and the clinical relevance of this effect (mean treatment effect 0.5%). A model was used to describe HbA1c over time, and the change in HbA1c at all time points (including week 48) was estimated from this model. Observations revised after changes in background antidiabetic drug or dose were included in the analysis. This analysis was expected to be unbiased because adjustments for background drug/dose were based on observed data (HbA1c, FPG), making revised data after drug change likely missing at random (MAR). Pooled data on increases (and decreases) in relation to background antidiabetic drug could be collected as an ancillary analysis of metabolic changes. A change in background antidiabetic medication was defined as a change in daily dose and/or the addition of a second agent.

Results

[178] Study population. Subjects included in this study were primarily Caucasian (76%) or Black/African American (20%). All subjects were overweight or obese (mean ± SD BMI 32.9 ± 3.4 kg/ ^m2 , range: 28-40), with approximately equal numbers of women (47%) and men (53%). All subjects had type 2 diabetes mellitus; mean HbA _1c was 7.99% (±1.025) and 7.66% (±0.950) in the bimagrumab and placebo groups, respectively. A total of 78 subjects were included, 37 in the bimagrumab group, of whom 14 were men (38%) and 23 were women (62%), and 38 in the placebo group, of whom 26 were men (68%) and 12 were women (32%). Baseline laboratory parameters were comparable between treatment groups. Mean body weight was 6.76 kg lower in the bimagrumab group compared with placebo. This difference was explained by a higher percentage of female patients in the bimagrumab group than in the placebo group.

[179] Body composition changes: A significant treatment effect of bimagrumab was observed on body composition at weeks 24 and 48 as measured by dual-energy x-ray absorptiometry (DXA). Significant reductions in total fat mass were observed in the bimagrumab group compared with placebo at both the week 24 and week 48 time points: -15.0% (-5.2 kg) in bimagrumab subjects compared with placebo at week 24 and -20.5% (7.3 kg) in bimagrumab subjects compared with placebo at week 48 (all p<0.001, Figure 8). This effect was observed as early as week 8 (the first post-dose scan) and was maintained through the end of the study at week 56. Significant reductions in body weight were also observed at week 48 in the bimagrumab group compared with placebo: -6.5% (5.9 kg) in the BYM338 group compared with -0.8% (0.8 kg) in the placebo group, p<0.001 (Figure 9A), resulting in a reduction in BMI of -6.7% (2.2 kg/ ^m2 ) in the BYM338 group compared with -0.8% (0.3 kg/ ^m2 ) in the placebo group, p<0.001 (Figure 9B). These effects were maintained through the end of the study at week 56.

[180] Insulin sensitivity and HbA _1c . The therapeutic effect of bimagrumab on HbA1c was a 0.76% [80% CI -1.05; 0.48] decrease compared with an increase of 0.04% [80% CI -0.23; 0.31] in the placebo group at week 48 (p=0.005). Insulin sensitivity was measured by both fasting insulin and glucose, as well as by a meal tolerance test. The therapeutic effect of bimagrumab on insulin sensitivity was significantly improved according to QUICKI (bimagrumab +0.01; placebo, unchanged, p=0.033) at week 36. There was a trend towards improvement in insulin sensitivity, measured by both the Matsuda index (bimagrumab +3.15, placebo +1.78, p=0.099) at week 48 and HOMA2-IR (bimagrumab -0.09; placebo +0.57, p=0.081).

[181] Fat distribution. A significant treatment effect with bimagrumab was observed in fat distribution at weeks 24 and 48 (Figure 10). A significant reduction in liver fat fraction (HFF) was observed at week 24 in the bimagrumab group compared with placebo: -4.6 percentage points over 24 weeks in the bimagrumab group compared with +0.23 percentage points in the placebo group, p= 0.006. At week 48, a significant reduction in HFF was observed in the bimagrumab group compared with placebo: 51.9% (-7 percentage points) over 48 weeks in the bimagrumab group compared with 18.3% (2.3 percentage points) in the placebo group, p= 0.01. The number of subjects who underwent MRI at week 48 is lower than at previous time points because the original protocol did not include MRI at week 48. MRI at this time point was added after completion of the interim analysis and after some subjects had already completed the study and no longer met the inclusion criteria for this assessment.

[182] Significant reductions in abdominal visceral fat were observed at week 24 in the bimagrumab group compared with placebo, a reduction of 1.49 L in the bimagrumab group compared with 0.22 L in the placebo group, p>0.001, and at week 48 -34.5% (1.5 L) in the BYM338 group compared with -0.2% (0.01 L) in the placebo group, p=0.08.

Discussion

[183] In the current study, only 7% weight loss was associated with a 52% reduction in liver fat in subjects receiving bimagrumab compared with 18% in subjects receiving placebo (both groups included dietary modification and exercise). This loss of liver fat is an unexpected finding based on previous observations in patients undergoing bariatric surgery (Phillips et al. (2007) Diabetes, Obesity and Metabolism, 10, 2008, 661–667) or dietary interventions (Lewis et al. (2006) Obesity Surgery, 16, 697–701), in which an average 10% weight loss results in a loss of approximately 30% of liver fat. In addition to reducing liver fat, bimagrumab treatment also reduced total body fat mass (primarily visceral fat), waist circumference, and HbA1c levels, while increasing lean body mass. These results are important because both type 2 diabetes and insulin resistance are important predictors of NAFLD/NASH progression to fibrosis and cirrhosis; reversing fatty liver disease will reduce the risk of type 2 diabetes and metabolic syndrome (reviewed in Cernea et al. Expert Rev Clin Pharmacol 2017). In addition, the increase in lean mass with bimagrumab therapy is important because patients with NASH are at increased risk of developing sarcopenia, which is the age-related loss of muscle mass and function (Koo et al. J Hepatology 2017; Petta et al. Ali Pharma Thera 2017; Carias et al. J Gastroenterol Hepatol 2016). Bimagrumab targets many of the metabolic abnormalities commonly found in people with obesity, T2D, and NASH.

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SEQUENCE LIST

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<120> TREATMENT OF LIVER DISEASE OR DISORDER,

PROPOSED USE OF ACTRII ANTAGONISTS

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<---

Claims (52)

1. Use of an antibody to an activin type II receptor (ActRII) or an antigen-binding fragment thereof for treating a liver disease or disorder in a subject in need thereof, wherein the liver disease or disorder is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and liver fibrosis, and wherein the antibody to an ActRII receptor or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDR1 of the sequence of SEQ ID NO: 1; a VH CDR2 of the sequence of SEQ ID NO: 2; a VH CDR3 of the sequence of SEQ ID NO: 3; a light chain variable domain (VL) CDR1 of the sequence of SEQ ID NO: 4; a VL CDR2 of the sequence of SEQ ID NO: 5; and a VL CDR3 of the sequence of SEQ ID NO: 6. 2. The use according to claim 1, wherein said subject has at least one condition selected from hepatic steatosis, lobular inflammation and hepatic ballooning. 3. The use according to claim 1 or 2, wherein said treatment reduces the fatty fraction of the liver in said subject compared to the fatty fraction of the liver in said subject before the treatment. 4. The use according to any one of claims 1-3, wherein said treatment reduces the NAFLD activity score (NAS) by at least 1 point, by at least 2 points, or by at least 3 points. 5. The use according to any one of claims 1-4, wherein said treatment reduces at least one of hepatosteatosis, liver inflammation and hepatic ballooning by at least 1 point on the NAS scale. 6. The use according to any one of claims 1-5, wherein said subject is a subject with diabetes mellitus, a subject with obesity, or a subject with metabolic syndrome or another metabolic disorder. 7. Use according to any one of paragraphs 1-6, wherein said subject has type 2 diabetes mellitus. 8. The use according to any one of paragraphs 1-7, wherein said subject is simultaneously receiving a standard treatment for type 2 diabetes mellitus. 9. The use according to claim 8, wherein the standard treatment agent is selected from metformin, a DPP4 inhibitor, metformin/DPP4 inhibitor, sulfonylureas, thiazolidinediones, GLP-1 receptor agonists, SGLT2 inhibitors, and an insulin therapy agent. 10. The use according to any one of claims 1-9, wherein the antibody to the ActRII receptor or antigen-binding fragment thereof is an antagonist of ActRIIA and/or ActRIIB. 11. The application according to paragraph 10, where a) an antibody to an ActRII receptor comprises an HC domain comprising SEQ ID NO:8 or a sequence with 95% identity thereto; b) an antibody to an ActRII receptor, comprising an LC domain comprising SEQ ID NO:7 or a sequence with 95% identity thereto; c) the antibody to the ActRII receptor comprises an HC domain comprising SEQ ID NO:8 or a sequence with 95% identity thereto, and an LC domain comprising SEQ ID NO:7 or a sequence with 95% identity thereto; d) the antibody to the ActRII receptor comprises a VL domain comprising SEQ ID NO:9, e) the antibody to the ActRII receptor comprises a VH domain comprising SEQ ID NO:10, or f) the antibody to the ActRII receptor comprises a VL domain comprising SEQ ID NO:9 and a VH domain comprising SEQ ID NO:10. 12. The use according to any of the preceding paragraphs, wherein the antibody to the ActRII receptor or antigen-binding fragment thereof is bimagrumab. 13. The use of claim 12, comprising administering from about 3 mg/kg to about 10 mg/kg of bimagrumab to said subject. 14. The use according to claim 12, comprising administering approximately 10 mg/kg bimagrumab to said subject. 15. Use according to any of paragraphs 12-14, wherein bimagrumab is administered every 4 weeks. 16. The use according to any one of claims 12-14, wherein bimagrumab is administered every 4 weeks for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. 17. The use according to any one of claims 1-16, comprising the administration of at least one additional therapeutic agent. 18. The use according to claim 17, comprising administering an antibody to ActRII or an antigen-binding fragment thereof in combination with at least one additional therapeutic agent for the treatment or prevention of liver disease. 19. The use according to claim 18, wherein at least one additional therapeutic agent is an FXR agonist, a steroyl-CoA desaturase-1 inhibitor, a THR-β agonist, a galectin-2 inhibitor, a PPAR agonist, a GLP-1 agonist, an FGF agonist, pyruvate synthase inhibitors, an apoptotic signal-regulated kinase 1 inhibitor, an acetyl-CoA carboxylase inhibitor, an FXR agonist, CCR inhibitor, thiazolidinedione, sodium-glucose cotransporter types 2 and 1 inhibitor, DPP-4 inhibitor, or any combination thereof. 20. The use according to claim 19, wherein the FXR agonist is selected from tropifexor, nidufexor, obeticholic acid, cilofexor, TERN-101, EYP001, EDP-305, AKN-083, INT-787, INT-767, AGN-242256 and MET409; the steroyl-CoA desaturase-1 inhibitor is arachidyl amidocholanic acid; the THR-β agonist is selected from MGL-3196, VK-2809 and MGL-3745; the galectin-2 inhibitor is GR-MD-02; the PPAR agonist is selected from saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, IVA337 and CER-002; the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, NC-101, G-49, ZP2929 and PB-718; the FGF agonist is selected from pegbelfermin, BMS-986171, NGM-282, NGM-313, YH25724 and tirzepatide; the pyruvate synthase inhibitor is nitazoxanide; the apoptotic signal-regulated kinase 1 inhibitor is selected from selensertib and GS-444217; the acetyl-CoA carboxylase inhibitor is selected from firsocostat, PF-05221304 and gemcaben; the FXR agonist is selected from M480, NTX-023-1 and INV-33; a CCR inhibitor is selected from AD-114, bertilimumab, CM-101, CCX-872, and cenicriviroc; a thiazolidinedione is selected from MSDC-0602K and pioglitazone; a sodium-glucose cotransporter-2/1 inhibitor is selected from remogliflozin, luseogliflozin, and dapagliflozin; or a DPP-4 inhibitor is selected from sitagliptin, saxagliptin, vildagliptin, linagliptin, evogliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, gosogliptin, and dutogliption. 21. Use of an antibody to the activin type II receptor (ActRII) or an antigen-binding fragment thereof for the manufacture of a medicament for the treatment of a liver disease or disorder in a subject in need thereof, wherein the liver disease or disorder is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and liver fibrosis, and wherein the antibody to the ActRII receptor or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDR1 of the sequence of SEQ ID NO: 1; a VH CDR2 of the sequence of SEQ ID NO: 2; a VH CDR3 of the sequence of SEQ ID NO: 3; a light chain variable domain (VL) CDR1 of the sequence of SEQ ID NO: 4; a VL CDR2 of the sequence of SEQ ID NO: 5; and a VL CDR3 of the sequence of SEQ ID NO: 6. 22. The use according to claim 21, wherein said subject has at least one condition selected from hepatic steatosis, lobular inflammation and hepatic ballooning. 23. The use according to claim 21 or 22, wherein said treatment reduces the fatty fraction of the liver in said subject compared to the fatty fraction of the liver in said subject before the treatment. 24. The use according to any one of claims 21-23, wherein said treatment reduces the NAFLD activity score (NAS) by at least 1 point, by at least 2 points, or by at least 3 points. 25. The use according to any one of claims 21-24, wherein said treatment reduces at least one of hepatosteatosis, liver inflammation and hepatic ballooning by at least 1 point on the NAS scale. 26. The use according to any one of claims 21-25, wherein said subject is a subject with diabetes mellitus, a subject with obesity, or a subject with metabolic syndrome or another metabolic disorder. 27. The use according to any of paragraphs 21-26, wherein said subject has type 2 diabetes mellitus. 28. The use according to any one of paragraphs 21-27, wherein said subject is simultaneously receiving a standard treatment for type 2 diabetes mellitus. 29. The use according to claim 28, wherein the standard treatment agent is selected from metformin, a DPP4 inhibitor, metformin/DPP4 inhibitor, sulfonylureas, thiazolidinediones, GLP-1 receptor agonists, SGLT2 inhibitors, and an insulin therapy agent. 30. The use according to any one of claims 21-29, wherein the antibody to the ActRII receptor or antigen-binding fragment thereof is an antagonist of ActRIIA and/or ActRIIB. 31. Application according to paragraph 30, where a) an antibody to an ActRII receptor comprises an HC domain comprising SEQ ID NO:8 or a sequence with 95% identity thereto; b) an antibody to an ActRII receptor, comprising an LC domain comprising SEQ ID NO:7 or a sequence with 95% identity thereto; c) the antibody to the ActRII receptor comprises an HC domain comprising SEQ ID NO:8 or a sequence with 95% identity thereto, and an LC domain comprising SEQ ID NO:7 or a sequence with 95% identity thereto; d) the antibody to the ActRII receptor comprises a VL domain comprising SEQ ID NO:9, e) the antibody to the ActRII receptor comprises a VH domain comprising SEQ ID NO:10, or f) the antibody to the ActRII receptor comprises a VL domain comprising SEQ ID NO:9 and a VH domain comprising SEQ ID NO:10. 32. The use according to any of the preceding claims, wherein the antibody to the ActRII receptor or antigen-binding fragment thereof is bimagrumab. 33. The use of claim 32, comprising administering from about 3 mg/kg to about 10 mg/kg of bimagrumab to said subject. 34. The use according to claim 32, comprising administering approximately 10 mg/kg bimagrumab to said subject. 35. Use according to any of paragraphs 32-34, wherein bimagrumab is administered every 4 weeks. 36. The use according to any one of claims 32-34, wherein bimagrumab is administered every 4 weeks for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. 37. The use according to any one of paragraphs 21-36, comprising the administration of at least one additional therapeutic agent. 38. The use according to claim 37, comprising administering an antibody to ActRII or an antigen-binding fragment thereof in combination with at least one additional therapeutic agent for the treatment or prevention of liver disease. 39. The use according to claim 38, wherein at least one additional therapeutic agent is an FXR agonist, a steroyl-CoA desaturase-1 inhibitor, a THR-β agonist, a galectin-2 inhibitor, a PPAR agonist, a GLP-1 agonist, an FGF agonist, pyruvate synthase inhibitors, an apoptotic signal-regulated kinase 1 inhibitor, an acetyl-CoA carboxylase inhibitor, an FXR agonist, CCR inhibitor, thiazolidinedione, sodium-glucose cotransporter types 2 and 1 inhibitor, DPP-4 inhibitor, or any combination thereof. 40. The use according to claim 39, wherein the FXR agonist is selected from tropifexor, nidufexor, obeticholic acid, cilofexor, TERN-101, EYP001, EDP-305, AKN-083, INT-787, INT-767, AGN-242256 and MET409; the steroyl-CoA desaturase-1 inhibitor is arachidyl amidocholanic acid; the THR-β agonist is selected from MGL-3196, VK-2809 and MGL-3745; the galectin-2 inhibitor is GR-MD-02; the PPAR agonist is selected from saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, IVA337 and CER-002; the GLP-1 agonist is selected from exenatide, liraglutide, semaglutide, NC-101, G-49, ZP2929 and PB-718; the FGF agonist is selected from pegbelfermin, BMS-986171, NGM-282, NGM-313, YH25724 and tirzepatide; the pyruvate synthase inhibitor is nitazoxanide; the apoptotic signal-regulated kinase 1 inhibitor is selected from selensertib and GS-444217; the acetyl-CoA carboxylase inhibitor is selected from firsocostat, PF-05221304 and gemcaben; the FXR agonist is selected from M480, NTX-023-1 and INV-33; a CCR inhibitor is selected from AD-114, bertilimumab, CM-101, CCX-872, and cenicriviroc; a thiazolidinedione is selected from MSDC-0602K and pioglitazone; a sodium-glucose cotransporter-2/1 inhibitor is selected from remogliflozin, luseogliflozin, and dapagliflozin; or a DPP-4 inhibitor is selected from sitagliptin, saxagliptin, vildagliptin, linagliptin, evogliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, gosogliptin, and dutogliption.

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