Combination therapy

Abstract

The present disclosure relates to the combined use of an ActRII pathway agent, such as an ActRII receptor antibody, and a GLP-1 agonist for the treatment of metabolic disorders, including obesity. As provided herein, the combined treatment reduces fat mass and maintains or increases lean mass.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 238,068, filed August 27, 2021, No. 63 / 301,012, filed January 19, 2022, and No. 63 / 333,351, filed April 21, 2022, the contents of which are incorporated by reference in their entireties.

[0002] Incorporation by reference of sequence listing The contents of the electronic sequence listing (VRNS_009_03WO_SeqList_ST26.xml, size: 10,557 bytes, created on: August 25, 2022) are incorporated herein by reference in their entirety. [Background technology]

[0003] Since the regulation of metabolism and fat accumulation involves complex biological feedback systems, the treatment of metabolic disorders such as obesity remains elusive.To date, drugs that are effective in regulating metabolic dysfunction often exhibit some side effects, which limit their usefulness in patient populations, especially in obese patient populations that require long-term treatment.Therefore, there is a need for additional compositions and methods for treating metabolic disorders, including obesity. Summary of the Invention

[0004] The present disclosure relates to the dual administration of an ActRII pathway agent, such as an ActRII receptor antagonist, such as an ActRII receptor antibody, and a glucagon-like peptide-1 receptor (GLP-1) agonist for the treatment of metabolic disorders. The combination therapy of the present disclosure, which comprises an ActRII pathway antibody and a GLP-1 agonist, has been found to reduce fat mass and maintain or increase lean mass. The combination therapy provided herein can improve metabolic dysfunction by reducing fat mass, increasing lean mass, improving glycemic control, and can also improve the tolerability and / or efficacy of one or both of these agents in a subject.

[0005] Provided herein is a method of treating a metabolic disorder in a subject, comprising administering to a subject in need thereof an ActRII receptor antibody and a glucagon-like peptide-1 receptor (GLP-1) agonist. In some embodiments, the metabolic disorder is selected from the group consisting of obesity, diabetes, metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, Prader-Willi syndrome, and monogenic disorders associated with obesity. In some embodiments, the diabetes is type I diabetes or type II diabetes.

[0006] In some embodiments, the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity resulting from mutations in one or more of the genes including ADCY3, ALMS1, ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BDNF, CCDC28B, CEP290, CREBBP, EP300, GNAS, IER3IP1, MC3R, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

[0007] In some embodiments, the treatment is useful for treating obesity-related comorbidities, the condition being selected from the group of impaired glucose tolerance, pre-diabetes, insulin resistance, high triglycerides, overweight-related physical disorders, osteoporosis, renal disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

[0008] In some embodiments, the subject has a body mass index (BMI) of 30 or greater. In some embodiments, the subject has a BMI of 27 or greater and has one or more obesity-related comorbidities. In some embodiments, the subject is overweight. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject is 45 years of age or older. In some embodiments, the subject is a child between 0 and 17 years of age.

[0009] In some embodiments, the treatment reduces body weight in a subject. In some embodiments, the treatment reduces fat mass in a subject. In some embodiments, the treatment increases lean mass in a subject. In some embodiments, the treatment reduces fat mass and increases lean mass in a subject. In some embodiments, the treatment reduces fat mass and preserves lean mass in a subject. In some embodiments, the treatment reduces central obesity in a subject. In some embodiments, the treatment improves glycemic control in a subject.

[0010] In some embodiments, treatment improves the safety, efficacy, and / or tolerability of the ActRII receptor antibody and / or glucagon-like peptide-1 receptor (GLP-1) agonist.

[0011] In some embodiments, the efficacy of treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA), waist circumference, reduction in BMI, waist-to-hip ratio, waist-to-height ratio, blood lipid profile, leptin, adiponectin, and adipsin levels, urinary biomarkers, hemoglobin A1c (HgbA1c) levels, hand dynamometry indicating muscle strength, glucose levels, insulin levels, Short Form (SPPB), Impact of Weight on Quality of Life (IWQoL-Lite for CT) assessment, Short Form (36) Health Survey (SF-36) assessment, Homeostasis Model Assessment 2 (HOMA2), and physical activity monitoring via actigraphy.

[0012] In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 1-6. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and comprises the amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto. In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and comprises the amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0013] In some embodiments, the antibody is specific to ActRIIA and ActRIIB.

[0014] In some embodiments, the GLP-1 agonist is an antibody, a small molecule, a peptide, or an aptamer.In some embodiments, the GLP-1 agonist is selected from the group consisting of exenatide, sustained release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, neuglutide, oxyntomodulin (e.g., mazudotide), retatortide, albiglutide, veinaglutide and PEG-loxenatide, pembidutide, and danugliplon.

[0015] In some embodiments, the GLP-1 agonist is a dual GLP-1 agonist and a GIP agonist. In some embodiments, the GLP-1 agonist is a dual GLP-1 agonist and a GCG agonist. In some embodiments, the GLP-1 agonist is a triagonist of the GIP / GLP-1 / glucagon receptor.

[0016] In some embodiments, the ActRII receptor antibody is administered at a dose of about 3 mg / kg to about 50 mg / kg. In some embodiments, the ActRII receptor antibody is administered at a dose of about 10 mg / kg to about 30 mg / kg. In some embodiments, the ActRII receptor antibody is administered at a dose of about 10 mg / kg. In some embodiments, the ActRII receptor antibody is administered at a dose of about 30 mg / kg. In some embodiments, the ActRII receptor antibody is administered at a dose of about 200 mg to about 400 mg once a week.

[0017] In some embodiments, the ActRII receptor antibody is administered at a dose of about 300 mg once a week.

[0018] In some embodiments, administration of the ActRII receptor antibody includes administration of at least one loading dose of the ActRII receptor antibody prior to administration of the ActRII receptor antibody and the GLP-1 agonist, on day 0 or week 0. In some embodiments, the loading dose of the ActRII receptor antibody is administered at a dose of about 10 mg / kg to about 30 mg / kg.

[0019] In some embodiments, the ActRII receptor antibody is administered at least once a day, at least once a week, at least twice a week, at least three times a week, at least once every two weeks, at least once every four weeks, at least once every six weeks, or at least once every 12 weeks. In some embodiments, the ActRII receptor antibody is administered at week 0, at about week 4, and at least once every 12 weeks thereafter.

[0020] In some embodiments, the GLP-1 agonist is administered at a dose of about 0.005 mg to about 3.0 mg weekly. In some embodiments, the GLP-1 agonist dose is gradually increased each week according to the following regimens: about 0.2 mg to about 3.0 mg, about 0.1 to about 1.0 mg, about 0.25 mg to about 2.4 mg, and about 0.25 mg to about 0.5 mg. In some embodiments, the GLP-1 agonist dose is administered at a dose of about 0.25 mg weekly from about week 0 to about week 4, followed by a dose of about 0.5 mg in week 5.

[0021] In some embodiments, the GLP-1 agonist dose is administered weekly at a dose of about 0.25 mg from about weeks 0 to about 4, at a dose of about 0.5 mg from about weeks 5 to about 8, at a dose of about 1.0 mg from about weeks 8 to about 12, at a dose of about 1.7 mg from about weeks 12 to about 15, at a dose of about 2.4 mg from about weeks 16 to about 20, and at a dose of about 2.4 mg from about weeks 20 onwards.

[0022] In some embodiments, the GLP-1 agonist dose is administered weekly at a dose of about 5.0 mg, about 10 mg, or about 15 mg.

[0023] In some embodiments, the ActRII receptor antibody and / or the GLP-1 agonist are administered intravenously. In some embodiments, the ActRII receptor antibody and / or the GLP-1 agonist are administered subcutaneously.

[0024] In some embodiments, the ActRII receptor antibody is administered before the GLP-1 agonist.In some embodiments, the ActRII receptor antibody is administered at least 12 weeks, at least 10 weeks, at least 8 weeks, at least 6 weeks, at least 4 weeks, at least 2 weeks, at least 1 week, at least 1 day, or at least 1 hour before the administration of the GLP-1 agonist.

[0025] In some embodiments, GLP-1 agonist is administered before ActRII receptor antibody.In some embodiments, GLP-1 agonist is administered at least 2 weeks, at least 1 week, at least 5 days, at least 4 days, at least 2 days, at least 1 day, at least 6 hours, or at least 1 hour before ActRII receptor antibody.In some embodiments, ActRII receptor antibody and GLP-1 agonist are administered simultaneously.

[0026] Also provided herein is a combination comprising an ActRII receptor antibody and a GLP-1 agonist.

[0027] In some embodiments, the ActRII receptor antibody comprises the amino acid sequence of SEQ ID NO: 1-6. In some embodiments, the ActRII receptor antibody comprises the amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and comprises the amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto. In some embodiments, the ActRII receptor antibody comprises the amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and comprises the amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0028] In some embodiments, the ActRII receptor antibody comprises a human IgG1 Fc domain with an alteration selected from the group consisting of 259I, 252Y, 307Q, 308F, 428L, 434H, 434F, 434Y, 434A, 434M, and 434S relative to the human IgG1 Fc domain according to the EU numbering scheme. In some embodiments, the ActRII receptor antibody comprises a human IgG1 Fc domain with an alteration selected from M428L and / or N434S relative to the human IgG1 Fc domain according to the EU numbering scheme.

[0029] Also provided herein is a pharmaceutical composition comprising a combination of an ActRII receptor antibody and a GLP-1 agonist, and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0030] [Figure 1] Figure 1 is a schematic diagram of a clinical trial designed to compare the effects on fat loss of bimagrumab, an exemplary ActRII receptor antibody, and semaglutide, a glucagon-like peptide-1 receptor (GLP-1) agonist, when given in combination or alone. The schematic includes a loading dose at week=0.

[0031] [Diagram 2] FIG. 2 is a summary of preclinical studies of the effects of ActRII receptor antibodies and GLP1 agonists in diet-induced obese mice.

[0032] [Diagram 3] FIG. 3 is a bar graph of the effects of circulating activin A, alone and in combination, with the GLP1 agonist semaglutide and ActRII receptor antibody in diet-induced obese mice.

[0033] [Figure 4A] Figures 4A-4C are bar graphs of the effects of the GLP1 agonist semaglutide and ActRII receptor antibody, alone and in combination, on fat mass measured by MRI, inguinal fat weight measured postmortem at the end of the study, and circulating leptin levels in diet-induced obese mice. [Figure 4B] Same as above. [Figure 4C] Same as above.

[0034] [Diagram 5] Figure 5 is a bar graph of the effect of the GLP1 agonist semaglutide and ActRII receptor antibody, alone and in combination, on lean muscle mass in diet-induced obese mice, assessed by weighing post-mortem gastrocnemius muscles at the end of the study.

[0035] [Figure 6]Figure 6 depicts changes in mRNA transcript levels assessed by RNAseq in inguinal fat of diet-induced obese mice in response to a combination of the GLP1 agonist semaglutide and an ActRII receptor antibody.

[0036] [Figure 7] Figure 7 is a line plot of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with an ActRII receptor antibody, on body weight over time, with varying doses of tirzepatide on day 11 in both tirzepatide groups to induce better food intake in diet-induced obese mice.

[0037] [Figure 8] Figure 8 is a line plot of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with an ActRII receptor antibody, on body fat over time as measured by MRI in diet-induced obese mice.

[0038] [Figure 9] Figure 9 is a bar graph of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with ActRII receptor antibody, on perirenal fat weight collected at the end of the study in diet-induced obese mice.

[0039] [Figure 10] FIG. 10 is a line plot of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with an ActRII receptor antibody, on food intake over time in diet-induced obese mice.

[0040] [Figure 11]FIG. 11 is a line plot of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with an ActRII receptor antibody, on lean mass over time in diet-induced obese mice.

[0041] [Figure 12A] Figure 12A is a line plot of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with an ActRII receptor antibody, on distance traveled in the quantitative open field test in diet-induced obese mice.

[0042] [Figure 12B] Figure 12B is a line plot of the effect of the GLP1 agonists semaglutide, tirzepatide, and liraglutide, alone and in combination with an ActRII receptor antibody, on speed in the quantitative open field test in diet-induced obese mice.

[0043] [Figure 13] FIG. 13 is a line plot of the effect of the GLP1 agonist tirzepatide, alone and in combination with an ActRII receptor antibody, on fat mass in diet-induced obese mice.

[0044] [Figure 14] FIG. 14 is a line plot of the effect of the GLP1 agonist tirzepatide, alone and in combination with an ActRII receptor antibody, on lean mass in diet-induced obese mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The compositions and methods of the present disclosure provide a combination comprising an ActRII pathway agent, for example, an ActRII receptor antagonist, for example, an ActRII receptor antibody, and a glucagon-like peptide-1 receptor (GLP-1) agonist for use in the treatment of metabolic disorders, including obesity.As provided herein, the combination significantly reduces fat mass and maintains or increases lean mass.

[0046] Both ActRII receptor antagonists and GLP-1 agonists induce a significant reduction in fat mass in human subjects of more than 20% over one year. However, ActRII receptor antagonists administered alone also increase lean mass, whereas GLP-1 agonists administered alone have the detrimental effect of decreasing lean mass.

[0047] The present disclosure demonstrates the surprising effect of combining an ActRII receptor antagonist and a glucagon-like peptide-1 receptor (GLP-1) agonist to result in a significant and synergistic reduction in fat mass while simultaneously maintaining or increasing lean mass.

[0048] I. Definition Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings commonly understood by those skilled in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell biology, immunology, pharmacology, and protein chemistry described herein are those well known and commonly used in the art.

[0049] It should be noted that as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "agent" refers to one or a mixture of such candidates, reference to a "method" includes reference to equivalent steps and methods known to those skilled in the art, and so forth.

[0050] As used herein, the term "approximately" or "about" when applied to one or more values ​​of interest refers to a value that is similar in magnitude to and / or within a similar range of a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of a stated reference value (except where such number exceeds 100% of possible values), unless otherwise stated or clear from the context.

[0051] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of that range, and any other stated or intervening value in that stated range, is encompassed within the invention unless the context clearly indicates otherwise. The upper and lower limits of these smaller ranges are also independently encompassed within the disclosure as being included in the smaller ranges, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included within the disclosure.

[0052] As used herein, the terms "polypeptide," "peptide," and "protein" refer to polymers of amino acids of any length. The terms also encompass amino acid polymers that have been modified to include, for example, disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component.

[0053] As used herein, the terms "identity" and "same" refer to the percentage of exact matching residues in the alignment of the sequence provided herein to the reference sequence, such as the alignment generated by the BLAST algorithm or other alignment algorithms known in the art. Identity may be calculated based on the alignment of the full-length sequence provided herein and the full-length reference sequence. Identity may also be calculated based on the partial alignment of the sequence provided herein and the reference sequence when the reference sequence is longer than the sequence provided herein. Identity may also be calculated based on the partial alignment of the sequence provided herein and the reference sequence when the reference sequence is shorter than the sequence provided herein. Thus, when aligning two sequences, as described above, a query sequence shares at least x% identity with a subject sequence if, in the alignment of the two sequences, at least x% (rounded down) of the residues in the subject sequence are aligned as exact matches with the corresponding residues in the query sequence, where the numerator is the number of exact matches and the denominator is the length of the query sequence. In some embodiments, the denominator may alternatively be the length of the query sequence minus any gaps of two or more mismatched residues. If the subject sequence has variable positions (e.g., residues designated with an X), alignment to any residue in the query sequence is counted as a match.

[0054] The terms "treatment", "treating" and the like are generally used herein to mean obtaining a desired pharmacological and / or physiological effect with a therapeutic agent. The effect may be prophylactic in that it completely or partially prevents the disease or its symptoms, e.g., it may reduce the likelihood that the disease or its symptoms will occur in a subject, and / or it may be therapeutic in that it completely or partially reduces the symptoms, or it may be a partial or complete cure for the disease and / or side effects caused by the disease. As used herein, "treatment" encompasses any treatment of a disease in a mammal, including (a) preventing the disease from occurring in a subject susceptible to, but not yet diagnosed as having, the disease, (b) inhibiting or delaying the onset or development of the disease, or (c) alleviating the disease, e.g., causing regression of the disease or symptoms associated with the disease. The therapeutic agent may be administered before, during, or after the onset of the disease. Treatment of an ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, may be of particular interest. In some embodiments, the treatment is performed before complete loss of function in the affected tissue. In some embodiments, the subject therapy is administered during the symptomatic stage of the disease, and in some embodiments, after the symptomatic stage of the disease.

[0055] The term "loading dose" refers to one or more doses of a therapeutic agent administered in addition to the combination therapy provided herein. As used herein, a "loading dose" can refer to one or more doses of an ActRII receptor antibody that is at the same concentration, a lower concentration, or a higher concentration than the dose of an ActRII receptor antibody that is part of the combination therapy.

[0056] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to any subject for which treatment or therapy is desired. The subject may be a mammalian subject. Mammalian subjects include, for example, humans, non-human primates, rodents (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, etc.), and the like. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, e.g., a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g., cat, dog).

[0057] As used herein, metabolic disorders refer to disorders affecting the dysregulation of mammalian metabolism, including, but not limited to, obesity, diabetes (types I and II), metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and obesity associated with monogenic disorders. Monogenic disorders associated with obesity in humans may include, but are not limited to, Bardet-Biedl syndrome, as well as disorders resulting from mutations in one or more of the following genes: ADCY3, ALMS1, ARL6, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, BDNF, CCDC28B, CEP290, CREBBP, EP300, GNAS, IER3IP1, MC3R, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B, or combinations thereof. Metabolic disorders may also be associated with complex genetic disorders, such as Prader-Willi syndrome.

[0058] As used herein, Body Mass Index or "BMI" refers to the unit of mass in kilograms (kg) divided by the unit of mass in square meters (m 2 As used herein, "obesity" in adult humans is defined as a body mass index (BMI) greater than or equal to 30 kg / m2, and is calculated as the body mass index (BMI) divided by the body height, rounded down to one decimal place. 2"Obesity" in humans is defined as a BMI equal to or greater than the age- and sex-specific 95th percentile of the CDC growth charts of 2000. The term "overweight" is defined as a BMI equal to or greater than 25 and equal to or less than 30.

[0059] "Obesity-related comorbidities", "obesity-related conditions" and "obesity-related disorders" may be used interchangeably and refer to health conditions that are dependent on the obesity of a subject. In some embodiments, an obesity-related comorbidity or condition increases the subject's risk of death. Comorbidities associated with obesity include, but are not limited to, high blood pressure (hypertension), high LDL cholesterol, low HDL cholesterol, high levels of triglycerides (dyslipidemia), type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, breathing problems, cancer, gastroesophageal reflux disease, severe COVID-19, all-cause mortality, poor quality of life, mental illnesses such as clinical depression, anxiety, and other mental disorders, and difficulties with physical pain and physical function.

[0060] "Lean mass" is defined as the subject's total body weight minus fat mass minus the subject's bone mass. Lean mass and fat mass may be measured, for example, by bioelectrical impedance analysis (BIA), magnetic resonance imaging (MRI) or dual energy X-ray absorptiometry (DXA).

[0061] As used herein, "antibody" includes reference to an immunoglobulin molecule that is immunologically reactive with a particular antigen, and includes both polyclonal and monoclonal antibodies. The term includes humanized antibodies, chimeric antibodies, e.g., murine variable regions with human constant regions, and conjugated antibodies. The term "antibody" also includes antigen-binding forms of antibodies, including fragments that retain antigen-binding ability (e.g., Fab', F(ab')2, Fab, single-chain variable fragments (scFv) containing VH and VL sequences linked together in a single chain, single-chain antibody fragments (scAb). Fragment crystallizable regions (Fc) may also be linked to any of the aforementioned antigen-binding fragments. The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies.

[0062] II. ActRII pathway modulators ActRII receptor antibody Activin receptor II B (ActRIIB) is a receptor for myostatin, activin, and bone morphogenetic protein (BMP). The interaction between myostatin and this receptor controls the inhibition of skeletal muscle differentiation via a Smad-dependent pathway. It is believed that by inhibiting or preventing myostatin from binding to ActRIIB, for example, via ActRII receptor antibodies, skeletal muscle formation can be induced. Regulation of activin receptor II A (ActRIIA) also plays a role in regulating muscle growth (Morvan et al. 2017).

[0063] Exemplary ActRII receptor antibodies that bind to ActRIIA and ActRIIB have been shown in human clinical trials to not only increase lean muscle mass, but also reduce fat mass and improve glycemic control (WO2010125003A1, WO2018116201A1, the contents of which are incorporated in their entirety, and Heymsfield et al. 2021;4(1):e2033457, JAMA). Exemplary ActRII receptor antibodies that may be used in some embodiments include the isolated, structurally characterized, human recombinant antibodies described in WO2010125003A1.

[0064] In some embodiments, an exemplary antibody of the disclosure comprises the sequence of bimagrumab (BYM338). The following table shows the relevant CDR, VH, VL, HC, and LC amino acid sequences for bimagrumab. [Table 1]

[0065] In some embodiments, an exemplary ActRII receptor antibody of the disclosure comprises a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO:1 (CDRH1), SEQ ID NO:2 (CDRH2), and SEQ ID NO:3 (CDRH3).

[0066] In some embodiments, an exemplary ActRII receptor antibody of the disclosure comprises a variable light chain comprising the CDR amino acid sequences of SEQ ID NO:4 (CDRL1), SEQ ID NO:5 (CDRL2), and SEQ ID NO:6 (CDRL3).

[0067] In some embodiments, an exemplary ActRII receptor antibody of the present disclosure comprises a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO:1 (CDRH1), SEQ ID NO:2 (CDRH2), and SEQ ID NO:3 (CDRH3), and a variable light chain comprising the CDR amino acid sequences of SEQ ID NO:4 (CDRL1), SEQ ID NO:5 (CDRL2), and SEQ ID NO:6 (CDRL3).

[0068] In some embodiments, an exemplary ActRII receptor antibody of the present disclosure comprises a variable heavy chain comprising an amino acid sequence of SEQ ID NO:7, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or a variable light chain comprising an amino acid sequence of SEQ ID NO:8, or an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0069] In some embodiments, an exemplary ActRII receptor antibody of the present disclosure comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 9, or an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or a light chain comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0070] In some embodiments, the ActRII receptor antibody of the present disclosure has an Fc domain, for example, a human IgG1 Fc domain, a human IgG2 Fc domain, a human IgG3 Fc domain, or a human IgG4 Fc domain. In some embodiments, the Fc domain is wild type. In some embodiments, the Fc domain is modified, for example, modified to increase serum half-life. In some embodiments, the Fc domain is a human IgG1 Fc domain and is modified to increase serum half-life. In some embodiments, the modification to increase serum half-life includes one or more of 259I, 252Y, 307Q, 308F, 428L, 434H, 434F, 434Y, 434A, 434M, and 434S compared to a human IgG1 Fc domain according to the EU numbering scheme. In some embodiments, the modifications include one or more of 259I / 434S, 308F / 434S, 308F / 428L / 434S, 259I / 308F / 434S, 307Q / 308F / 434S, 250I / 308F / 434S, and 308F1319L / 434S relative to the human IgG1 Fc domain, according to the EU numbering scheme.

[0071] In some embodiments, the ActRII receptor antibody binds to ActRIIB with a KD of 100 nM or less, 10 nM or less, 1 nM or less. Preferably, the ActRII receptor antibody binds to ActRIIB with an affinity of 100 pM or less (i.e., 100 pM, 50 pM, 10 pM, 1 pM or less). In some embodiments, the ActRII receptor antibody binds to ActRIIB with an affinity of 10-20 pM.

[0072] In some embodiments, the ActRII receptor antibody binds to ActRIIB with an affinity that is 5 times higher, more preferably 10 times higher, even more preferably 50 times higher, and even more preferably 100 times higher than ActRIIA. In some embodiments, the ActRII receptor antibody binds to ActRIIA with an affinity of 100 pM or greater (i.e., 250 pM, 500 pM, 1 nM, 5 nM or greater).

[0073] Other ActRII pathway agents In other embodiments, the combination therapy described herein comprises an agent that binds to ActrRII receptor ligand, for example, directly binds to myostatin or activin. Such agents include, but are not limited to, myostatin inhibitors (e.g., myostatin antibodies, or myostatin small molecule antagonists), activin inhibitors (e.g., activin antibodies, or activin small molecule antagonists), or the soluble extracellular portion of ActRIIB or ActRIIA that can act as "ligand sink", optionally further stabilized with Fc. Thus, in some embodiments, the present disclosure provides a method for treating metabolic disorders, comprising administering to a subject in need thereof an ActrII pathway agent (other than ActRII receptor antibodies) in combination with a GLP-1 agonist, wherein the agent is selected from the group consisting of myostatin inhibitors, activin inhibitors, or soluble portions of ActRII receptors.

[0074] In some embodiments, administration of both an ActRII pathway agent (other than an ActRII receptor antibody) and a GLP-1 agonist shows beneficial effects, and the ActRII pathway agent (other than an ActRII receptor antibody) administered as part of a treatment with a GLP-1 agonist reduces the dosage of the GLP-1 agonist required to see an effect and / or increases the therapeutic effect of the GLP-1 agonist compared to the GLP-1 agonist alone. In some embodiments, the beneficial effect is that the GLP-1 agonist reduces the dosage of the ActRII pathway agent (other than an ActRII receptor antibody) required to see an effect and / or increases the therapeutic effect of the ActRII pathway agent compared to administration of the ActRII pathway agent alone. In some embodiments, the beneficial effect is an increased safety of the combination compared to the ActRII pathway agent or GLP-1 agent alone. In some embodiments, the beneficial effect is an increased efficacy of the combination compared to the ActRII pathway agent or GLP-1 agent alone. In some embodiments, the beneficial effect is increased tolerability compared to the ActRII pathway agent or the GLP-1 agent alone.

[0075] III. GLP-1 agonists The glucagon-like peptide-1 receptor is a pancreatic beta cell receptor that stimulates insulin secretion upon binding of the hormone glucagon-like peptide 1 (GLP-1). GLP-1 is a type of incretin hormone, all of which control insulin release in response to blood glucose. GLP-1 agonists mimic the action of the GLP-1 peptide, activating the GLP-1 receptor upon binding and stimulating insulin secretion.

[0076] However, GLP-1 agonists have significant side effects and tolerability problems at effective doses.GLP-1 agonists have also been shown to reduce lean body mass in subjects during treatment.Cautions and precautions for GLP-1 agonists (e.g., semaglutide) include, but are not limited to, thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, hypoglycemia, acute kidney injury, severe adverse gastrointestinal reactions, hypersensitivity, such as anaphylactic reactions and angioedema, diabetic retinopathy, a complication in type 2 diabetes subjects, increased heart rate, and suicidal behavior and thoughts.Adverse reactions reported in at least 5% of subjects treated with GLP-1 agonists (e.g., semaglutide) include nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, hives, hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, and gastroesophageal reflux disease. Thus, there is a need for optimized dosing and treatment with GLP-1 agonists.

[0077] As provided herein, the GLP-1 agonist of the present disclosure can be peptide, antibody, small molecule, or aptamer.In some embodiments, the GLP-1 agonist is peptide or peptide analog, including but not limited to exenatide, sustained release exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, neuglutide, cotadutide, oxyntomodulin, or pembidutide.In some embodiments, the GLP-1 agonist is a small molecule non-peptide agonist, such as danugliplon.

[0078] In some embodiments, the GLP-1 agonist is a dual agonist that binds to and activates or inactivates a second receptor in addition to the GLP-1 receptor, the second receptor being a glucose-dependent insulinotropic (GIP) receptor or a glucagon (GCG) receptor. An exemplary dual-acting GLP-1 agonist that binds to both the GLP-1 receptor and the GIP receptor is tirzepatide. An exemplary dual-acting GLP-1 agonist that binds to both the GLP-1 receptor and the GCG receptor is cotadutide, neuglutide, and oxyntomodulin, which are included in the present disclosure as possible therapeutic agents that can be used in combination with ActRII receptor antibodies. In some embodiments, the GLP-1 agonist is also a GIP antagonist. In some embodiments, the GLP-1 agonist is also a GCG antagonist.

[0079] In some embodiments, the GLP-1 agonist is a GIP / GLP-1 / Glucagon receptor triagonist, for example, a GGG triagonist, for example, LY343794.

[0080] IV. Combination Therapy Combination therapy, or "combination," contemplated herein includes co-administration of an ActRII receptor antibody (or other ActRII pathway agent) with a GLP-1 agonist, which may be administered before, after, or simultaneously with the GLP-1 agonist. Such combination therapy may further include an initial loading dose of an ActRII receptor antibody (or other ActRII pathway agent). In an exemplary embodiment, the co-administration includes administering an ActRII receptor antibody comprising the amino acid sequence of SEQ ID NO: 1-6 and / or SEQ ID NO: 7 and 8 (or a sequence having at least 90% sequence identity thereto). In a further exemplary embodiment, the co-administration includes administering an ActRII receptor antibody comprising the sequence of SEQ ID NO: 1-6 and / or SEQ ID NO: 7 and 8 (or a sequence having at least 90% sequence identity thereto), and any of the GLP-1 agonists semaglutide, tirzepatide, or liraglutide.

[0081] The combination therapy of the present disclosure, which comprises an ActRII receptor antibody and a GLP-1 agonist, may be administered via any route.In some embodiments, the ActRII receptor antibody and / or the GLP-1 agonist are delivered orally, subcutaneously, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, intravaginally, intrarectally, or intraocularly.In an exemplary embodiment, the ActRII receptor antibody is administered intravenously (IV) and / or subcutaneously, and the GLP-1 agonist is administered subcutaneously.

[0082] Dosage and timing of ActRII receptor antibodies in combination therapy In the combination therapies contemplated herein, in some embodiments, an ActRII receptor antibody is administered to a subject in need thereof at a dose of about 3 mg / kg of the subject's body weight to about 50 mg / kg of the subject's body weight.

[0083] In some embodiments, the ActRII receptor antibody is administered intravenously to the subject at a dose of about 3 mg / kg of the subject's body weight to about 50 mg / kg of the subject's body weight.

[0084] In some embodiments, the ActRII receptor antibody is administered to a subject in need thereof at a dose of about 3 mg / kg, in some embodiments, at a dose of about 4 mg / kg, in some embodiments, at a dose of about 5 mg / kg, in some embodiments, at a dose of about 6 mg / kg, in some embodiments, at a dose of about 7 mg / kg, in some embodiments, at a dose of about 8 mg / kg, in some embodiments, at a dose of about 9 mg / kg, in some embodiments, at a dose of about 10 mg / kg, in some embodiments, at a dose of about 11 mg / kg, and in some embodiments, at a dose of about 12 mg / kg. In some embodiments, at a dose of about 13 mg / kg, in some embodiments, at a dose of about 14 mg / kg, in some embodiments, at a dose of about 15 mg / kg, in some embodiments, at a dose of about 16 mg / kg, in some embodiments, at a dose of about 17 mg / kg, in some embodiments, at a dose of about 18 mg / kg, in some embodiments, at a dose of about 19 mg / kg, in some embodiments, at a dose of about 20 mg / kg, in some embodiments, at a dose of about 21 mg / kg, in some embodiments, at a dose of about 22 mg / kg, and in some embodiments, at a dose of about 23 mg / kg. In some embodiments, at a dose of about 24 mg / kg, in some embodiments, at a dose of about 25 mg / kg, in some embodiments, at a dose of about 26 mg / kg, in some embodiments, at a dose of about 27 mg / kg, in some embodiments, at a dose of about 28 mg / kg, in some embodiments, at a dose of about 29 mg / kg, in some embodiments, at a dose of about 30 mg / kg, in some embodiments, at a dose of about 31 mg / kg, in some embodiments, at a dose of about 32 mg / kg, in some embodiments, at a dose of about 33 mg / kg, and in some embodiments, at a dose of about 34 mg / kg. g / kg, in some embodiments at a dose of about 35 mg / kg, in some embodiments at a dose of about 36 mg / kg, in some embodiments at a dose of about 37 mg / kg, in some embodiments at a dose of about 38 mg / kg, in some embodiments at a dose of about 39 mg / kg, in some embodiments at a dose of about 40 mg / kg, in some embodiments at a dose of about 41 mg / kg, in some embodiments at a dose of about 42 mg / kg, in some embodiments at a dose of about 43 mg / kg, in some embodiments at a dose of about 44 mg / kg,In some embodiments, the compound is administered at a dose of about 45 mg / kg, in some embodiments, at a dose of about 46 mg / kg, in some embodiments, at a dose of about 47 mg / kg, in some embodiments, at a dose of about 48 mg / kg, in some embodiments, at a dose of about 49 mg / kg, and in some embodiments, at a dose of about 50 mg / kg.

[0085] In some embodiments, the ActRII receptor antibody is administered to a subject in need thereof at a dose of 10 mg / kg. In some embodiments, the ActRII receptor antibody is administered to a subject in need thereof at a dose of 30 mg / kg. In some embodiments, the ActRII receptor antibody is administered intravenously to a subject in need thereof at a dose of 10 mg / kg. In some embodiments, the ActRII receptor antibody is administered intravenously to a subject in need thereof at a dose of 30 mg / kg.

[0086] In some embodiments, the ActRII receptor antibody is administered to a subject in need thereof two, three, four, or five or more times. In some embodiments, the ActRII receptor antibody is administered in a dosing regimen of once a week, twice a week, three times a week, once every two weeks, once every four weeks, once every six weeks, once every 12 weeks, or once every 15 weeks. In some embodiments, the ActRII receptor antibody is administered every quarter of the year. In some embodiments, the ActRII receptor antibody is administered at a dose of about 10 mg / kg every 12 weeks. In some embodiments, the ActRII receptor antibody is administered at a dose of 30 mg / kg every 12 weeks.

[0087] In some embodiments, the ActRII receptor antibody is administered intravenously at a dose of about 10 mg / kg every 12 weeks. In some embodiments, the ActRII receptor antibody is administered intravenously at a dose of 30 mg / kg every 12 weeks.

[0088] In some embodiments, the ActRII receptor antibody is administered at a dosage regimen of about 100 to about 600 mg once, twice, three or more times per week. In some embodiments, the ActRII receptor antibody is administered at a dosage regimen of about 200 to about 400 mg, e.g., about 300 mg, once, twice, three or more times per week, or once every two weeks.

[0089] In some embodiments, the ActRII receptor antibody is administered subcutaneously in a dosage regimen of about 200 to about 400 mg. In an exemplary embodiment, the ActRII receptor antibody is administered subcutaneously at a dose of about 300 mg.

[0090] In some embodiments, the ActRII receptor antibody is administered at a dose of about 200 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of about 200 mg once a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 200 mg twice a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 200 mg three times a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 200 mg every two weeks. In some embodiments, the ActRII receptor antibody is administered subcutaneously at a dose of about 200 mg.

[0091] In an exemplary embodiment, the ActRII receptor antibody is administered at a dose of about 300 mg. In an exemplary embodiment, the ActRII receptor antibody is administered at a dose of about 300 mg once a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 300 mg twice a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 300 mg three times a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 300 mg every two weeks. In an exemplary embodiment, the ActRII receptor antibody is administered subcutaneously at a dose of about 300 mg. In an exemplary embodiment, the ActRII receptor antibody is administered subcutaneously at a dose of about 300 mg once a week.

[0092] In some embodiments, the ActRII receptor antibody is administered at a dose of about 400 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of about 400 mg once a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 400 mg twice a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 400 mg three times a week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 400 mg every two weeks. In some embodiments, the ActRII receptor antibody is administered subcutaneously at a dose of about 400 mg once a week.

[0093] In some embodiments, the ActRII receptor antibody is administered at a dose of 600 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 600 mg once a week, twice a week, or three times a week, or every two weeks. In some embodiments, the ActRII receptor antibody is administered subcutaneously at a dose of about 600 mg.

[0094] In some embodiments, the ActRII receptor antibody is administered subcutaneously at a dosage regimen of about 600 mg to about 3000 mg, e.g., about 1000 mg, once, twice, three or four times per month. In some embodiments, the ActRII receptor antibody is administered subcutaneously at a dosage regimen of about 600 to about 3000 mg. In some embodiments, the ActRII receptor antibody is administered subcutaneously at a dosage regimen of about 600 mg to about 3000 mg, once, twice, three or four times per month.

[0095] In some embodiments, the ActRII receptor antibody is administered at a dose of 750 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 750 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 900 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 900 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 1050 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1050 mg once a month.

[0096] In some embodiments, the ActRII receptor antibody is administered at a dose of 1200 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1200 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 1350 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1350 mg once a month.

[0097] In some embodiments, the ActRII receptor antibody is administered at a dose of 1500 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1500 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 1650 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1650 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 1800 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1800 mg once a month.

[0098] In some embodiments, the ActRII receptor antibody is administered at a dose of 1950 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 1950 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 2100 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 2100 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 2250 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 2250 mg once a month.

[0099] In some embodiments, the ActRII receptor antibody is administered at a dose of 2400 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 2400 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 2550 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 2550 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 2700 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 2700 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 2850 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 2850 mg once a month. In some embodiments, the ActRII receptor antibody is administered at a dose of 3000 mg. In some embodiments, the ActRII receptor antibody is administered at a dose of 3000 mg once a month.

[0100] loading dose In some embodiments, administering a loading dose of ActRII receptor antibody in addition to combination therapy can improve the outcome of combination therapy.Without being bound by theory, it is believed that administering a loading dose can maintain the level of ActRII receptor antibody in the serum of subjects over time, and further optimize combination therapy.Therefore, in some embodiments, a loading dose of ActRII receptor antibody is administered.

[0101] In some embodiments, one or more loading doses of the ActRII receptor antibody are administered to a subject in need thereof on day 0 or week 0 prior to the start of the combination therapy. In some embodiments, one or more loading doses of the ActRII receptor antibody are provided 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks prior to the administration of the combination therapy. In an exemplary embodiment, the loading dose is administered about 4 weeks prior to the start of the combination therapy.

[0102] In some embodiments, the second administration of the one or more loading doses is administered about 6 months, about 8 months, about 10 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, or about 24 months after administration of the combination therapy. In some embodiments, the one or more loading doses are administered periodically or periodically in addition to the combination therapy. In an exemplary embodiment, the loading dose is first administered about 4 weeks before the start of the combination therapy and about one year thereafter.

[0103] In some embodiments, the subject is administered one or more loading doses followed by the combination therapy, and then a second round of treatment, e.g., a second administration of one or more loading doses followed by repeated combination therapy; similarly, treatment can further include a third set of one or more loading doses followed by a third round of combination therapy, etc.

[0104] In some embodiments, the loading dose is a dose of ActRII receptor antibody at the same concentration, a lower concentration, or a higher concentration than the dose of ActRII receptor antibody administered in the combination therapy. Thus, the loading dose may be about 3 mg / kg of subject's body weight to about 50 mg / kg of subject's body weight, or any amount therebetween. In some embodiments, the loading dose is administered intravenously at a dose of about 3 mg / kg of subject's body weight to about 50 mg / kg of subject's body weight.

[0105] In some embodiments, the loading dose of the ActRII receptor antibody is administered to a subject in need thereof at a dose of about 3 mg / kg, in some embodiments, at a dose of about 4 mg / kg, in some embodiments, at a dose of about 5 mg / kg, in some embodiments, at a dose of about 6 mg / kg, in some embodiments, at a dose of about 7 mg / kg, in some embodiments, at a dose of about 8 mg / kg, in some embodiments, at a dose of about 9 mg / kg, in some embodiments, at a dose of about 10 mg / kg, in some embodiments, at a dose of about 11 mg / kg, and in some embodiments, at a dose of about 12 mg / kg. In some embodiments, at a dose of about 13 mg / kg, in some embodiments, at a dose of about 14 mg / kg, in some embodiments, at a dose of about 15 mg / kg, in some embodiments, at a dose of about 16 mg / kg, in some embodiments, at a dose of about 17 mg / kg, in some embodiments, at a dose of about 18 mg / kg, in some embodiments, at a dose of about 19 mg / kg, in some embodiments, at a dose of about 20 mg / kg, in some embodiments, at a dose of about 21 mg / kg, in some embodiments, at a dose of about 22 mg / kg, and in some embodiments, at a dose of about 23 mg / kg. In some embodiments, at a dose of about 24 mg / kg, in some embodiments, at a dose of about 25 mg / kg, in some embodiments, at a dose of about 26 mg / kg, in some embodiments, at a dose of about 27 mg / kg, in some embodiments, at a dose of about 28 mg / kg, in some embodiments, at a dose of about 29 mg / kg, in some embodiments, at a dose of about 30 mg / kg, in some embodiments, at a dose of about 31 mg / kg, in some embodiments, at a dose of about 32 mg / kg, in some embodiments, at a dose of about 33 mg / kg, and in some embodiments, at a dose of about 34 mg / kg. In some embodiments, at a dose of about 35 mg / kg, in some embodiments, at a dose of about 36 mg / kg, in some embodiments, at a dose of about 37 mg / kg, in some embodiments, at a dose of about 38 mg / kg, in some embodiments, at a dose of about 39 mg / kg, in some embodiments, at a dose of about 40 mg / kg, in some embodiments, at a dose of about 41 mg / kg, in some embodiments, at a dose of about 42 mg / kg, in some embodiments, at a dose of about 43 mg / kg, in some embodiments, at a dose of about 44 mg / kg,In some embodiments, the compound is administered at a dose of about 45 mg / kg, in some embodiments, at a dose of about 46 mg / kg, in some embodiments, at a dose of about 47 mg / kg, in some embodiments, at a dose of about 48 mg / kg, in some embodiments, at a dose of about 49 mg / kg, and in some embodiments, at a dose of about 50 mg / kg.

[0106] In an exemplary embodiment, the ActRII receptor antibody loading dose is about 10 mg / kg of subject body weight. In another exemplary embodiment, the ActRII receptor antibody loading dose is about 30 mg / kg of subject body weight. In some embodiments, the ActRII receptor loading dose of about 10 mg / kg of subject body weight is administered subcutaneously. In some embodiments, the ActRII receptor loading dose of about 10 mg / kg of subject body weight is administered intravenously. In some embodiments, the ActRII receptor loading dose is about 30 mg / kg of subject body weight and is administered intravenously.

[0107] In some exemplary embodiments, the loading dose of the ActRII receptor antibody is about 200-400 mg per administration. In some exemplary embodiments, the loading dose of the ActRII receptor antibody is about 300 mg per administration. In some exemplary embodiments, the loading dose of the ActRII receptor antibody is about 200-400 mg per administration and is administered subcutaneously.

[0108] Dosage and timing of GLP-1 agonists in combination therapy In some embodiments of the combination therapy contemplated herein, the GLP-1 agonist is administered to a subject in need thereof at a dose of about 0.005 mg to about 3.0 mg, e.g., about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, or about 3.0 mg. In an exemplary embodiment, the GLP-1 agonist is administered subcutaneously to a subject in need thereof at a dose of about 0.005 mg to about 3.0 mg.

[0109] In other embodiments of the combination therapy, the GLP-1 agonist is administered to a subject in need thereof at a weekly dose of about 1 to about 20 mg, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In an exemplary embodiment, the GLP-1 agonist is administered subcutaneously to a subject in need thereof at a dose of about 5 mg, about 10 mg, or about 15 mg.

[0110] In some embodiments, the GLP-1 agonist is gradually increased according to one of the following regimens, for example, from about 0.2 mg to about 3.0 mg, from about 0.1 to about 1.0 mg, from about 0.25 mg to about 2.4 mg, or from about 0.25 mg to about 0.5 mg. In some embodiments, the GLP-1 agonist is administered to a subject in need thereof at a dose of 0.5 mg. In some embodiments, the GLP-1 agonist is administered to a subject in need thereof at a dose of 1.0 mg. In some embodiments, the GLP-1 agonist is administered to a subject in need thereof at a dose of 1.7 mg. In some embodiments, the GLP-1 agonist is administered to a subject in need thereof at a dose of 2.4 mg.

[0111] In some exemplary embodiments, the GLP-1 agonist is administered incrementally and subcutaneously.

[0112] In some embodiments, the GLP-1 agonist is administered daily, every 2nd day, every 3rd day, every 4th day, every 5th day, every 6th day, every week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 0.5 mg. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 1.0 mg to a subject in need thereof. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 1.7 mg to a subject in need thereof. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 2.4 mg. In some embodiments, the GLP-1 agonist is administered weekly at a dose of about 0.25 mg from about week 0 to about week 4, and at a dose of about 0.5 mg from week 5 onward. In some embodiments, the GLP-1 agonist dose is administered weekly at a dose of about 0.25 mg from about weeks 0 to about 4, at a dose of about 0.5 mg from about weeks 5 to about 8, at a dose of about 1.0 mg from about weeks 8 to about 12, at a dose of about 1.7 mg from about weeks 12 to about 15, at a dose of about 2.4 mg from about weeks 16 to about 20, and at a dose of about 2.4 mg weekly from about week 20 onwards.

[0113] In some embodiments, the GLP-1 agonist is administered every day, every 2nd day, every 3rd day, every 4th day, every 5th day, every 6th day, every week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 5 mg. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 10 mg. In some embodiments, the GLP-1 agonist is administered once a week at a dose of 15 mg.

[0114] Combination Therapy - Exemplary Dosing Regimens In some exemplary embodiments, the combination therapy of ActRII receptor antibody and GLP-1 agonist comprises a loading dose of ActRII receptor antibody administered at week 0, followed by a dose of about 30mg / kg of ActRII receptor antibody administered intravenously 4 weeks after the loading dose and every 12 weeks thereafter during the course of treatment, and a GLP-1 agonist administered subcutaneously every week.In some embodiments, the GLP-1 agonist is administered at a dose of about 2.4mg or a dose of about 15mg every week.In some exemplary embodiments, the GLP-1 agonist of the combination therapy, such as semaglutide, is administered at a dose of about 2.4mg every week.In some embodiments, the GLP-1 agonist, such as semaglutide, is administered at a dose of about 0.5mg every week.In some embodiments, the GLP-1 agonist, such as semaglutide, is administered at a dose of about 1.0mg every week. In some embodiments, the GLP-1 agonist, for example, semaglutide, is administered at a dose of about 2mg every week.In other preferred embodiments, the GLP-1 agonist, for example, tirzepatide, of the combination therapy is administered at a dose of about 15mg every week.In other embodiments, the GLP-1 agonist, for example, tirzepatide, is administered at a dose of about 5mg every week.In other embodiments, the GLP-1 agonist, for example, tirzepatide, is administered at a dose of about 10mg every week.

[0115] In other exemplary embodiments, the combination therapy of ActRII receptor antibody and GLP-1 agonist comprises an ActRII receptor antibody subcutaneously administered once a week, twice a week, or once every two weeks at a dose of about 300 mg, and a GLP-1 agonist subcutaneously administered weekly.In some exemplary embodiments, the GLP-1 agonist is administered weekly at a dose of about 2.4 mg or at a dose of about 15 mg.In some exemplary embodiments, the GLP-1 agonist of the combination therapy, such as semaglutide, is administered weekly at a dose of about 2.4 mg.In some embodiments, the GLP-1 agonist, such as semaglutide, is administered weekly at a dose of about 0.5 mg.In some embodiments, the GLP-1 agonist, such as semaglutide, is administered weekly at a dose of about 1.0 mg. In some embodiments, the GLP-1 agonist, for example, semaglutide, is administered at a dose of about 2mg every week.In another exemplary embodiment, the GLP-1 agonist of the combination therapy, for example, tirzepatide, is administered at a dose of about 15mg every week.In another embodiment, the GLP-1 agonist, for example, tirzepatide, is administered at a dose of about 5mg every week.In another embodiment, the GLP-1 agonist, for example, tirzepatide, is administered at a dose of about 10mg every week.

[0116] Combination Therapy – Timing In some embodiments, the ActRII receptor antibody is administered at least 12 weeks, at least 10 weeks, at least 8 weeks, at least 6 weeks, at least 4 weeks, at least 2 weeks, at least 1 week, at least 1 day, or at least 1 hour before the administration of the GLP-1 agonist.The ActRII receptor antibody administration regimen may be further preceded by administration of a loading dose.

[0117] In some embodiments, the GLP-1 agonist is administered at least 2 weeks, at least 1 week, at least 5 days, at least 4 days, at least 3 days, at least 2 days, at least 1 day, at least 6 hours, or at least 1 hour before the antibody.

[0118] In some embodiments, the ActRII receptor antibody is administered at a dose of about 10 mg / kg every 12 weeks, optionally in two or more doses, and the GLP-1 agonist is administered at a dose of about 0.5 mg to 2.4 mg every week. In some embodiments, the ActRII receptor antibody is administered at a dose of about 300 mg once a week, in two or more doses, and the GLP-1 agonist is administered at a dose of about 0.5 mg to 2.4 mg every week. In some embodiments, administration of the GLP-1 agonist begins before the first administration of the ActRII receptor antibody. In some embodiments, administration of the GLP-1 agonist begins after the first administration of the ActRII receptor antibody. The ActRII receptor antibody administration regimen may be further preceded by administration of a loading dose.

[0119] In some embodiments, the ActRII receptor antibody and the GLP-1 agonist are co-administered, i.e., administered simultaneously.In some embodiments, the ActRII receptor antibody and the GLP-1 agonist are co-formulated and co-administered simultaneously in a single injection.The ActRII receptor antibody administration regimen can be further preceded by administration of a loading dose.

[0120] Subjects and Treatment As described herein, the combination therapy is useful for treating metabolic disorders in a subject in need thereof. Metabolic disorders of the present disclosure include, but are not limited to, obesity (e.g., glucocorticoid-induced obesity), diabetes (type I or type II diabetes), metabolic syndrome, Prader-Willi syndrome, and hypertrophic lipodystrophy. In an exemplary embodiment, the metabolic disorder is treated with an ActRII receptor antibody comprising a sequence of SEQ ID NO: 1-6 and / or SEQ ID NO: 7 and 8, or a sequence having at least 90% sequence identity thereto, and a GLP-1 agonist selected from semaglutide, tirzepatide, and liraglutide.

[0121] In some embodiments, the subject who needs the combination treatment described herein is an overweight subject.In some embodiments, the subject who needs the combination treatment described herein comprises the subject who has BMI 30 or more.In some embodiments, the subject who needs treatment comprises the subject who has BMI 27 or more and has obesity-related comorbidities.

[0122] In some embodiments, the subject in need of treatment lacks glycemic control.

[0123] The subject may be of any age, including young. In some embodiments, the subject is over 20 years old, over 30 years old, over 40 years old, over 45 years old, over 50 years old, over 60 years old, or over 80 years old. In exemplary embodiments, the subject is over 45 years old. In some embodiments, the subject is over 18 years old.

[0124] In an exemplary embodiment, the ActRII receptor antibody is administered as part of a treatment program with a GLP-1 agonist. In some embodiments, administration of both the ActRII receptor antibody and the GLP-1 agonist treats one or more metabolic disorders, such as obesity and obesity-related conditions. In some embodiments, the obesity-related conditions include, but are not limited to, one or more of impaired glucose tolerance, prediabetes, insulin resistance, high triglycerides, overweight-related physical disorders, osteoporosis, renal disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, gastroesophageal reflux disease, and / or gallstones.

[0125] In some embodiments, administration of both an ActRII receptor antibody and a GLP-1 agonist improves glycemic control and / or treats type II diabetes.

[0126] In some embodiments, administration of both an ActRII receptor antibody and a GLP-1 agonist shows beneficial effects, and an ActRII receptor antibody administered as part of a treatment with a GLP-1 agonist reduces the dosage of the GLP-1 agonist required to see an effect and / or increases the therapeutic effect of the GLP-1 agonist compared to the GLP-1 agonist alone. In some embodiments, a beneficial effect is shown in which the GLP-1 agonist reduces the dosage of the ActRII receptor antibody required to see an effect and / or increases the therapeutic effect of the ActRII receptor antibody compared to administration of the ActRII receptor antibody alone. In some embodiments, the beneficial effect is an increase in the safety of the combination of an ActRII receptor antibody and a GLP-1 agonist compared to either an ActRII receptor antibody or a GLP-1 agent alone. In some embodiments, the beneficial effect is an increase in the efficacy of the combination of an ActRII receptor antibody and a GLP-1 agonist compared to either an ActRII receptor antibody or a GLP-1 agent alone.

[0127] In some embodiments, the increased safety and / or tolerability of the drug is determined by a 100%, 90%, 80%, 75%, 50%, or 25% lower risk of adverse reactions, side effects, number of cautions and precautions, or number of contraindications. In some embodiments, the level of patient- or physician-reported side effects of the GLP-1 agonist is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold when the GLP-1 agonist is administered as part of a treatment with an ActRII receptor antibody compared to the GLP-1 agonist alone. In some embodiments, the beneficial effect is an increased efficacy of the combination of the ActRII receptor antibody and the GLP-1 agonist compared to either the ActRII receptor antibody or the GLP-1 agent alone.

[0128] In some embodiments, combination treatment with an ActRII receptor antibody and a GLP-1 agonist exhibits an additive therapeutic effect, such that administration of both agents increases the efficacy of the treatment.

[0129] In some embodiments, combination treatment with an ActRII receptor antibody and a GLP-1 agonist exhibits a synergistic therapeutic effect, such that administration of both agents increases efficacy beyond the sum of the effects of each agent individually.

[0130] As provided herein, combination treatment of an ActRII receptor antibody and a GLP-1 agonist reduces fat mass in a subject. In some embodiments, the treatment reduces fat mass in a subject (compared to before treatment) by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 8 At least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%. In some embodiments, the combination treatment of ActRII receptor antibody and GLP-1 agonist reduces fat mass in an additive or synergistic manner.

[0131] In some embodiments, combination treatment of an ActRII receptor antibody and a GLP-1 agonist increases lean mass in a subject. In some embodiments, the treatment reduces lean mass in a subject by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50% over the treatment period. In some embodiments, the combination treatment increases fat mass and decreases lean mass to a greater extent than treatment with a GLP-1 agonist alone.

[0132] In some embodiments, the combination treatment of an ActRII receptor antibody and a GLP-1 agonist reduces fat mass and increases lean mass in a subject. In some embodiments, the combination treatment of an ActRII receptor antibody and a GLP-1 agonist reduces fat mass and increases lean mass in an additive or synergistic manner. In some embodiments, the treatment reduces fat mass in a subject by at least 5% (e.g., 5% to 50%) and increases lean mass by at least 5% (e.g., 5% to 50%) over the treatment period.

[0133] In some embodiments, the combination treatment of the ActRII receptor antibody and the GLP-1 agonist maintains lean mass in the subject. In some embodiments, the combination treatment of the ActRII receptor antibody and the GLP-1 agonist reduces fat mass and maintains lean mass in the subject in an additive or synergistic manner. In some embodiments, the combination treatment reduces fat mass in the subject by at least 5% (e.g., 5% to 50%) and maintains lean mass over the treatment period.

[0134] In some embodiments, the combination treatment of ActRII receptor antibody and GLP-1 agonist reduces body weight in a subject.In some embodiments, the treatment reduces body weight in a subject by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% over the treatment period.In some embodiments, the combination treatment reduces body weight to a greater extent than either treatment alone.

[0135] In some embodiments, the combination treatment of ActRII receptor antibody and GLP-1 agonist reduces the BMI of the subject.In some embodiments, the treatment reduces the BMI of the subject by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% over the treatment period.In some embodiments, the combination treatment reduces BMI to a greater extent than either treatment alone.

[0136] In some embodiments, the combination treatment of an ActRII receptor antibody and a GLP-1 agonist reduces body weight in a synergistic manner. In some embodiments, the combination treatment of an ActRII receptor antibody and a GLP-1 agonist reduces central obesity in a subject. In some embodiments, the treatment reduces central obesity in a subject by at least 5% (e.g., 5% to 50%) over the treatment period. In some embodiments, the combination treatment reduces central obesity to a greater extent than either treatment alone. In some embodiments, the combination treatment of an ActRII receptor antibody and a GLP-1 agonist reduces central obesity in a synergistic manner.

[0137] In some embodiments, the combination treatment of ActRII receptor antibody and GLP-1 agonist reduces waist circumference in subjects.According to the Centers for Disease Control and Prevention (CDC), the average waist circumference of women in the United States is 38.7 inches, and the average waist circumference of men is 40.2 inches.In some embodiments, waist circumference can be reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% over the treatment period.

[0138] In some embodiments, fat mass in response to combination treatment with an ActRII receptor antibody and a GLP-1 agonist is measured using BIA and / or DXA.

[0139] In some embodiments, the combination treatment of ActRII receptor antibody and GLP-1 agonist improves glycemic control in subjects.In some embodiments, the combination treatment improves glycemic control to a higher degree than either treatment alone.In some embodiments, the combination treatment of ActRII receptor antibody and GLP-1 agonist improves glycemic control in a synergistic manner.

[0140] In some embodiments, glycemic control in response to combination treatment of an ActRII receptor antibody and a GLP-1 agonist is measured by glucose and insulin levels and applies the HOMA2 model (www.dtu.ox.ac.uk / homacalculator / ).

[0141] In some embodiments, the increased efficacy of the combination effect in a subject is determined by at least a two-fold, at least a three-fold, at least a four-fold, at least a five-fold, at least a ten-fold, or at least a twenty-fold improvement in at least one of the following measurements, compared to either treatment alone: ​​body weight, bioelectrical impedance analysis (BIA) of lean mass and / or fat mass, waist-to-hip ratio, waist-to-height ratio, dual-energy x-ray absorptiometry (DXA) of lean mass and / or fat mass, waist circumference, reduction in BMI, blood lipid profile, leptin, adiponectin, and adipsin levels, IL-8 and / or IL-6 levels, urinary biomarkers, hemoglobin A1c (HgbA1c) levels, hand dynamometry indicating muscle strength, glucose levels, insulin levels, Short Form (SPPB), Impact of Weight on Quality of Life (IWQoL-Lite for CT) assessment, Short Form (36) Health Survey (SF-36) assessment, Homeostasis Model Assessment 2 (HOMA2), and physical activity monitoring via actigraphy.

[0142] V. Pharmaceutical Combinations In some embodiments, the ActRII receptor antibody and the GLP-1 agonist are combined in a pharmaceutical composition. In an exemplary embodiment, the composition comprises an ActRII receptor antibody comprising the sequences of SEQ ID NOs: 1-6 and / or SEQ ID NOs: 7 and 8 (or sequences having at least 90% sequence identity thereto), and the GLP-1 agonist semaglutide. In another exemplary embodiment, the composition comprises an ActRII receptor antibody comprising the sequences of SEQ ID NOs: 1-6 and / or SEQ ID NOs: 7 and 8 (or sequences having at least 90% sequence identity thereto), and the GLP-1 agonist tirzepatide.

[0143] In some embodiments, the composition comprises an excipient or carrier, for example, an aqueous carrier. A variety of aqueous carriers can be used, for example, buffered saline. The composition may contain pharma- ceutically acceptable auxiliary substances as necessary to approximate physiological conditions, such as pH and buffering agents, toxicity counteracting agents, for example, disodium phosphate dihydrate, monosodium phosphate, sodium acetate, sodium chloride, potassium chloride, calcium chloride, hydrochloric acid, sodium hydroxide, L-histidine, L-histidine chloride, and sodium lactate. The concentration of active agent in these formulations can vary and is selected based on fluid volume, viscosity, and body weight according to the specific mode of administration selected and the needs of the patient (e.g., Remington's Pharmaceutical Science (15th ed., 1980) and Goodman&Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., eds., 1996)). The compositions may contain pharma- ceutically acceptable auxiliary substances, such as those that contribute to the stability and activity of the pharmacologically active agent or agents, including, but not limited to, trehalose, sucrose, or other sugars and polysorbate 20, polysorbate 60, polysorbate 80 or other emulsifiers or stabilizers. EXAMPLES

[0144] Example 1: Safety and efficacy of bimagrumab versus semaglutide in overweight or obese adults The randomized, placebo-controlled trial was designed to compare the safety and efficacy of bimagrumab with that of open-label semaglutide in adults aged 45 years and older who are overweight or obese.The objective of the study is to compare the effects of bimagrumab and semaglutide, administered in combination or alone, on fat loss in adults aged 45 years and older who are obese or overweight with at least one obesity-related comorbidity.

[0145] Main purpose To evaluate whether the combination of bimagrumab and semaglutide is superior to either therapy administered alone in terms of fat mass loss measured by change in waist circumference (cm) from baseline from weeks 0 to 24. The study may be extended to weeks 28, 48, 68, or 72. Secondary Objectives I. To evaluate the safety and tolerability of bimagrumab and semaglutide when administered in combination and as monotherapy. II.To evaluate the effect of the combination of bimagrumab and semaglutide compared with each therapy administered alone on change in lean mass from baseline (kg and % change) from week 0 to week 24 as measured by DXA. III. To evaluate whether the combination of bimagrumab and semaglutide is superior to either therapy administered alone in terms of change from baseline in muscle strength measured by hand dynamometry from weeks 0 to 24. IV.To evaluate the effect of the combination of bimagrumab and semaglutide compared with each therapy administered alone on change in fat mass (kg and % change) from baseline from week 0 to week 24 as measured by DXA. V. To evaluate the change from baseline in weight (kg) and body composition, as measured by bioelectrical impedance analysis (BIA), from weeks 0 to 24 in each treatment group. VI. To assess the proportion of participants in each treatment group experiencing ≥ 5% weight loss from baseline from Week 0 to Week 24 (%). VII. To evaluate change from baseline in systolic and diastolic blood pressure (mmHg) from Week 0 to Week 24 for each treatment group. VIII. To evaluate change from baseline in HbA1C and HOMA2 from Week 0 to Week 24 for each treatment group. IX. To determine the change in all above objective primary and secondary endpoints from Week 24 to Week 36. X. To assess change from baseline in participants' health status (SF-36) from Week 0 to Week 24. XI. To assess the change from baseline to weeks 0 to 24 in participants' quality of life (IWQoL-Lite for CT).

[0146] Efficacy endpoints To determine the efficacy of the combination of bimagrumab and semaglutide on fat mass loss, the following markers will be evaluated: waist circumference, blood pressure, fat mass by DXA, lean mass by DXA, weight, BMI, lipids, HgbA1c levels, glucose levels, insulin levels, Short Physical Performance Battery (SPPB), physical activity monitoring via actigraphy, exploratory urinary biomarkers, leptin, adiponectin, adipsin, IL-18, and IL-6 as adipose tissue biomarkers, and activin A as a pharmacodynamic (PD) biomarker.

[0147] Safety evaluation items To determine the safety of treatment, clinically determined adverse events (AEs) will be monitored, including but not limited to treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Additionally, changes from baseline in patient health markers from week 0 to week 24 will be monitored, including heart rate (bpm), amylase (U / L), lipase (U / L), alkaline phosphatase ALP (U / L), aspartate aminotransferase AST (U / L), and alanine aminotransferase ALT (U / L).

[0148] Test Design The study is randomized, partially blinded, and placebo-controlled, with a nine-arm, multicenter design. Participants will be randomized to one of the following treatment arms: a) Bimagrumab 30mg / kg b) bimagrumab placebo c) Low-dose semaglutide (0.5mg / 1.0mg) + bimagrumab 30mg / kg d) High-dose semaglutide (2.4 mg) + bimagrumab 30 mg / kg e) Low-dose semaglutide (0.5 mg / 1.0 mg) + bimagrumab placebo f) High-dose semaglutide (2.4 mg) + bimagrumab placebo g) Bimagrumab 10 mg / kg h) Low-dose semaglutide (0.5 mg / 1.0 mg) + bimagrumab 10 mg / kg i) High-dose semaglutide (2.4 mg) + bimagrumab 10 mg / kg

[0149] The bimaglutide and bimagrumab placebo treatments will remain blinded, and the semaglutide treatment will be open-label. The study will consist of a screening visit to assess eligibility, followed by clinic visits and phone contacts every 6 weeks during treatment until follow-up at week 24. An end-of-study visit will take place at week 36.

[0150] Investigational drug, dosage and mode of administration As described above in the study design, bimagrumab will be administered by intravenous (IV) infusion at either 10 mg / kg or 30 mg / kg doses every 12 weeks for a total of two doses. The rationale for the 24-week exposure period and assessment of the primary endpoint is that this period allows time to observe the differential effects of the two bimagrumab doses and the two semaglutide doses versus each other and versus placebo.

[0151] Weekly subcutaneous injections of semaglutide The dose of semaglutide will be gradually increased from 0.25mg to 2.4mg weekly for the high-dose group, or from 0.25mg to 0.5mg weekly for the low-dose group, according to the label instructions. The control group for semaglutide will be an untreated group, with no subcutaneous injections.

[0152] Reference therapy, dosage and mode of administration Bimagrumab placebo will be administered by IV infusion in 5% dextrose in water (D5W) for two doses, the first at week 0 and the second at week 12.

[0153] Test period The study will be of maximum 40 weeks duration, including a 4-week screening period, a 24-week treatment period, and a 12-week follow-up period. Selection Criteria 1. Written informed consent must be obtained prior to any study-related evaluations. 2. Men ≥ 18 years old, women ≥ 40 years old. 3. BMI ≥ 30 or BMI ≥ 27 with one or more obesity-related comorbidities. 4. Have a stable weight (± 3 kg) within three months of screening. 5. Self-reported at least one weight loss dietary disorder 6. Able to communicate satisfactorily with the investigator, comply with study requirements, and adhere to the diet and activity program for the duration of the study. Exclusion criteria 1. History of severe reaction to monoclonal antibody therapy 2. Use of other investigational drugs at the time of enrollment or within 30 days or 5 half-lives of enrollment, whichever is longer, or as required by other restrictions on study participation based on local regulations. 3. Previous severe hypersensitivity reaction to semaglutide or any of the excipients in Ozempic or Wegovy. 4. Patient weight >150kg 5. History of any clinically significant condition, e.g., cardiovascular disease, pulmonary disease or osteoarthritis, that prevents regular walking for exercise. 6. Deficit of 500 calories per day, no high protein diet. 7. Pregnant or breastfeeding women. 8. Females of childbearing potential, defined as any female of physiological reproductive potential, who must use highly effective contraception during treatment and for 6 months after the final dose of bimagrumab. Highly effective contraceptive methods include: i. Total Abstinence. Periodic abstinence (e.g., calendar, ovulation, symptomatic, postovulatory methods) and withdrawal are not acceptable methods of contraception. ii. Female sterilization (bilateral surgical oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks prior to initiation of study treatment. In the case of oophorectomy alone, only if female reproductive status has been confirmed by follow-up hormone level evaluation. iii. Male sterilization (at least 6 months prior to screening). For female participants in this study, the vasectomized male partner must be the participant's only partner. iv. Any two combinations of the following methods (a+b or a+c or b+c): a) Oral, injectable or implant hormonal contraception or other forms of hormonal contraception with equivalent effectiveness (failure rate <1%), such as a hormonal vaginal ring or transdermal hormonal contraception. b) Intrauterine contraceptive devices or intrauterine contraceptive devices. c) Barrier contraception methods, e.g. condoms or occlusive caps (diaphragms or cervical / tubal caps) with spermicidal foams / gels / films / creams / vaginal suppositories.

[0154] If using oral contraceptives, women must have been taking the same pill steadily for at least 3 months prior to receiving study treatment.

[0155] Women are considered to be postmenopausal and of no childbearing potential if they have had natural amenorrhea for 12 months with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) or have had bilateral surgical oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior. In the case of oophorectomy alone, women are considered of no childbearing potential only if follow-up hormone level evaluation has confirmed their reproductive status. 9. History of treated or untreated malignancy of any organ system within the past five years, with or without evidence of local recurrence or metastasis, except for non-melanoma skin cancer treated with local therapy, prostate cancer managed with watchful waiting, or breast or cervical cancer treated with local excision alone. 10. Personal or family history of medullary thyroid carcinoma or history of a patient with polyendocrine neoplasia type 2 syndrome. 11. Disease other than cancer known to cause cachexia or muscle wasting, disease known to cause GI malabsorption disease associated with lipodystrophy. 12. Diagnosis of diabetes and current use of any antidiabetic medication. Do not exclude metabolic syndrome, even if controlled with antidiabetic medications such as metformin or SGLT2 inhibitors. 13. Uncontrolled hypothyroidism. Hypothyroid patients treated with hormone replacement therapy must be on a stable dose for at least 6 weeks prior to the screening visit. 14. Significant psychiatric disorder, clinically evident peripheral vascular disease or disorder, or systemic disorder that may affect any of the efficacy evaluations (e.g., diabetic neuropathy, chronic fatigue syndrome, schizophrenia, bipolar disorder, severe depression, intermittent claudication). 15. Known heart failure classified as New York Heart Association Class III and IV or chronic hypotension (systolic blood pressure <100 mmHg). 16. Systolic blood pressure >180 or <90mmHg, or diastolic blood pressure >100 or <50mmHg at screening, or malignant hypertension. 17. ECG showing clinically significant abnormalities, including uncontrolled ventricular response at rest (mean heart rate >100 beats per minute [bpm]) despite medical or device therapy, or any history of spontaneous or inducible sustained ventricular tachycardia (heart rate >100 bpm for 30 seconds) despite medical or device therapy, or any history of resuscitated cardiac arrest or the presence of an automatic internal myocardial stimulator-defibrillator. 18. History of unstable angina, myocardial infarction, coronary artery bypass surgery, or percutaneous coronary intervention (e.g., angioplasty or stent placement) within 180 days prior to the screening visit. 19. Long QT syndrome or QTcF>450 ms (Fridericia corrected) for men and QTcF>470 ms for women at baseline at screening or repeat assessment. 20. Significant blood coagulation disorder, 75,000 / mm 3 platelet count less than 1.0 g / dL, and hemoglobin less than 11.0 g / dL. 21. Liver disease or liver injury as indicated by abnormal liver function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum bilirubin (except Gilbert's disease). Investigators must adhere to the following criteria: No single transaminase should exceed 3x the upper limit of normal (ULN). Any single parameter elevated to 3x ULN should be rechecked as soon as possible and in all cases at least before randomization to rule out laboratory error. If the total bilirubin concentration increases above 1.5 × ULN, then the total bilirubin should be differentiated into direct and indirect reacting bilirubin. In either case, serum bilirubin should not exceed a value of 1.6 mg / dL (27 μmol / L). 22. History or presence of severe acute or chronic liver disease (compensated or uncompensated), known gallbladder or bile duct disease, acute or chronic pancreatitis, stage 3 or worsening acute or chronic renal failure. 23. History of hepatitis B or HIV. Successfully treated hepatitis A or C is not excluded. 24. Use of any prescription medications known to adversely affect muscle mass, including antiandrogens (e.g., luteinizing hormone releasing hormone (LHRH) agonists), antiestrogens (e.g., tamoxifen), etc. Low-dose estrogen replacement therapy in postmenopausal women is acceptable, and 5-alpha reductase inhibitors in men is acceptable. 25. Lack of peripheral venous access. 26. Donation or loss of ≥400 mL of blood within 8 weeks prior to first dose, or more if required by local regulations, or plasma donation (>250 mL) within 14 days prior to first dose. 27. Any acute illness within 30 days prior to the screening visit that, in the investigator's opinion, affects lower extremity function or the patient's ability to participate in the study. 28. Smoking more than one pack of cigarettes per day. 29. Marijuana use more than twice a week. 30. Consumption of 5 or more alcoholic drinks on the same occasion on each of 5 or more days during the past 30 days.

[0156] Example 2: Safety and efficacy of bimagrumab versus semaglutide in overweight or obese adults The study described in Example 1 to compare the safety and efficacy of bimagrumab with open-label semaglutide in overweight or obese adults aged 45 years or older can be modified as described herein. Unlike Example 2, this dosing paradigm includes administration of a loading dose.

[0157] Secondary Objectives The secondary objects described in Example 1 are incorporated herein, and additional secondary objects include: XII.To evaluate the effect of the combination of bimagrumab and semaglutide compared with each therapy administered alone using change in bioimpedance from baseline (percent change in ohms) from weeks 0 to 24. XIII. To determine changes in all primary and secondary objectives from Week 24 to Week 36.

[0158] Efficacy endpoints The efficacy endpoints described in Example 1 were incorporated herein, with additional efficacy endpoints including lipid levels (total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG)), urinary microalbumin levels, the Impact of Weight on Quality of Life (IWQoL-Lite for CT) assessment, and the Short-Form (36) Health Survey (SF-36) assessment.

[0159] Test Design The study involves clinic visits and phone calls every 4 weeks during the treatment phase.

[0160] Investigational drug, dosage and mode of administration Bimagrumab is administered at doses of 10 mg / kg (low dose) or 30 mg / kg (high dose) by intravenous (IV) infusion at weeks 0 (loading dose), 4, and 16. This dosing regimen is every 12 weeks and includes a loading dose at week 0 prior to the start of the week 4 dosing regimen.

[0161] Weekly subcutaneous injections of semaglutide As described in Example 1, the dose of semaglutide is gradually increased according to label instructions for the high dose group from 0.25 mg to 2.4 mg weekly, or from 0.25 mg to 0.5 mg weekly for the low dose group.

[0162] Dose escalation of semaglutide for the low dose group may be as follows: 0.25 mg from weeks 0 to 4, then 0.5 mg.

[0163] Dose escalation of semaglutide for the high dose group is as follows: 0.25 mg weekly from weeks 0 to 4, 0.5 mg weekly from weeks 5 to 8, 1.0 mg weekly from weeks 8 to 12, 1.7 mg weekly from weeks 12 to 15, 2.4 mg weekly from weeks 16 to 20, and 2.4 mg weekly from weeks 20 to 24. Patients unable to tolerate weekly doses of 0.5 mg or higher may be reduced to the preceding lower dose.

[0164] Exclusion criteria The exclusion criteria described in Example 1 were incorporated herein, with additional exclusion criteria for study participants including a history of familial hypertriglyceridemia or fasting triglycerides greater than 500 mg / dl (5.65 mmol / L).

[0165] Example 3: Effects of combined treatment with ActRII receptor antibody and glucagon-like peptide-1 receptor (GLP-1) antibody on fat and lean mass in obese mice: A pilot study In overweight and obese patients, the ActRII receptor antibody bimagrumab and the glucagon-like peptide-1 receptor (GLP-1) semaglutide have each been shown to induce greater than 20% body fat loss over approximately one year. However, bimaglutide caused a 4-8% increase in muscle mass, and semaglutide caused loss of lean mass. Mouse experiments were designed to determine the efficacy of the combination of bimagrumab and semaglutide on fat loss and to determine the extent to which bimagrumab can attenuate the loss of lean mass associated with semaglutide therapy. The present disclosure describes the surprising result that combined treatment with the ActRII receptor antibody bimagrumab and the glucagon-like peptide-1 receptor (GLP-1) semaglutide reduced fat mass to a greater extent than the ActRII receptor antibody alone in obese mice, while also increasing lean mass.

[0166] method Five- to six-week-old C57Bl / 6J mice were fed a 60% fat diet for 14 weeks as an obese mouse model, reaching a mean body weight of 49 grams at the start of treatment. Using a modified 3x3 factorial design, groups of mice (n=8 per group) received daily subcutaneous (sc) treatment with 0.3 mg / kg or 20 mg / kg bimagrumab, CDD866, intraperitoneally (ip), and / or 5 μg / kg or 40 μg / kg semaglutide. The high-fat diet was continued throughout the treatment period, and food intake and body weight were monitored twice weekly. Clinical findings, body composition by MRI, and physical activity were assessed weekly.

[0167] result Mice treated with semaglutide alone or with CDD866 had an initial reduction in food intake that returned to above baseline by 2 weeks, at which point there were no clinical observations of concern in any of the animals. Indeed, animals receiving the higher doses of both drugs tended to be more active than the vehicle-only group. In mice receiving a 20mg / kg dose of CDD866 alone, lean mass increased by 13%. For the same 20mg / kg dose of CDD866 combined with a 40μg / kg dose of semaglutide, lean mass increased by 5%, compared to a 4% lean mass reduction with semaglutide 40μg / kg alone. Fat mass after 2 weeks of treatment was reduced by 8% with the 20mg / kg dose of CDD866 and 16% with the 40μg / kg dose of semaglutide alone. Notably, fat mass was reduced by 31% in mice receiving 20mg / kg CDD866 in combination with 40μg / kg semaglutide.When administered together, bimagrumab and semaglutide have at least additive efficacy in reducing fat in obese mice, with a concomitant increase in lean mass.

[0168] Example 4: Pharmacokinetic effects of the combination of ActRII receptor antibody CDD866 and glucagon-like peptide-1 receptor (GLP-1) semaglutide The study was designed to determine the effect of CDD866 on semaglutide pharmacokinetics (PK), and the effect of semaglutide on CDD866 PK. Notably, CDD866 and semaglutide each had a minimal effect on the overall exposure of the other, as assessed by AUC. method A dedicated cohort of diet-induced obese (DIO) mice was used. Blood samples were collected at five time points with three mice per time point. Table 1 shows the effect of CDD866 at a dose of 20 mg / kg on semaglutide PK at a dose of 40 μg / kg. [Table 2]

[0169] Table 2 below shows the effect of semaglutide administered at a dose of 40 μg / kg on CDD866 PK administered at a dose of 20 mg / kg. [Table 3]

[0170] Example 5: Effects of combined treatment with ActRII receptor antibody, CDD866, and GLP-1 agonist semaglutide on fat and lean mass in mice: An extension study The present disclosure provides surprising results showing that the combination of an ActRII receptor antibody and a GLP-1 agonist synergistically reduces fat mass while also maintaining or increasing lean mass.

[0171] As described above in Example 3, mouse experiments were designed to determine the effectiveness of the combination of ActRII receptor antibody and GLP-1 agonist in fat loss and to determine the extent to which ActRII receptor antibody can attenuate the lean mass loss associated with GLP-1 agonist treatment.As shown in Table 3 below, the combination of ActRII receptor antibody CDD866 and GLP-1 agonist semaglutide synergistically reduced fat mass and increased lean mass in DIO mice compared to controls. [Table 4]

[0172] As described in the study summary in Figure 2, efficacy measures of the ActRII receptor antibody and GLP-1 agonist combination included food consumption, body weight, clinical biomarkers, MRI, and physical activity levels in DIO mice during the 3 weeks of treatment.

[0173] The pharmacodynamics (PD) of the ActRII receptor antibody was evaluated in the presence of semaglutide. As shown in Figure 3, there was little effect of the GLP-1 agonist semaglutide on CDD866 regulation of circulating activin A levels in the blood. These results indicate that GLP-1 agonists do not interfere with ActRII receptor antibody function.

[0174] Notably, CDD866 in combination with semaglutide administered to DIO mice showed at least additive effects on inguinal fat mass and leptin levels, as well as a synergistic effect on fat mass loss (Figures 4A-4C, Table 3). Furthermore, CDD866 in combination with semaglutide reversed the lean mass muscle loss of semaglutide alone (Figure 5). These results indicate that the combination of CDD866 and the GLP-1 agonist semaglutide provides both a synergistic reduction in fat mass loss and also serves to counter the reduction in lean mass exhibited by the GLP-1 agonist alone.

[0175] We also performed RNAseq of inguinal adipose tissue RNA transcripts. The RNAseq transcript results are shown in Figure 6 and are consistent with a reduction in fat mass in adipocytes via lipid mobilization signaling. The RNA libraries for the RNAseq experiments contained approximately 44-73 million reads per sample, and the 20 genes with the greatest changes in transcript levels in response to the combination of CDD866 and semaglutide are shown in Figure 6. These results indicate that the combination of CDD866 and semaglutide activates lipid mobilization and reduces new lipid storage in adipose tissue.

[0176] Example 6: Effects of combined treatment with ActRII receptor antibody, CDD866, and an additional GLP-1 agonist on fat and lean mass in mice To determine whether other GLP-1 agonists could similarly function to reduce fat mass synergistically with ActRII receptor antagonists, the GLP-1 semaglutide, liraglutide, and tirzepatide were tested in combination with CDD 866. The combination of the ActRII receptor antagonist CDD866 and the GLP-1 agonist tirzepatide resulted in an even greater synergistic reduction in fat mass loss compared to that of semaglutide, while further increasing lean mass compared to controls.

[0177] method DIO mice were administered CDD866, a murine version of bimagrumab, at 20 mg / kg intraperitoneally (ip) weekly in combination with semaglutide (40 μg / kg once daily), liraglutide (40 μg / kg twice daily), or subcutaneous tirzepatide (45 μg / kg once daily, and from day 11 onwards, 22.5 μg once daily). The GLP-1 agonists were not dose-escalated in this study. The tirzepatide dose was lowered to 22.5 μg / kg on day 11, resulting in a moderate observed reduction in food intake.

[0178] result Combinations of ActRII receptor antibody CDD866 with each of the three different GLP-1 agonists semaglutide, liraglutide, and tirzepatide all resulted in greater weight loss than either CDD866 or the GLP-1 agonist alone (Figure 7). Combinations with each GLP-1 agonist resulted in at least additive reductions in body fat measured by MRI (Figure 8) or by weighing perirenal fat measured by nephroscopy (Figure 9). Table 4 below shows that the combination of the ActRII receptor antagonist CDD866 and the GLP-1 agonist tirzepatide resulted in a significant synergistic reduction in fat mass loss while further increasing lean mass compared to the control. [Table 5]

[0179] Figures 13 and 14 show the significant effect of the combination of CDD866 and tirzepatide on fat mass loss and lean mass maintenance and / or gain.

[0180] The combination of CDD866 and each of the GLP-1 agonists also significantly reduced food intake, which is associated with fat loss (Figure 10). Although we expected that the increase in lean mass would be minimal when caloric intake was restricted, CDD866 in combination with each of the GLP-1 agonists showed reduced lean mass loss compared to the GLP-1 agonist alone (Figure 11). Indeed, mice treated with CDD866 in combination with each of the GLP-1 agonists also showed longer open field distances and faster locomotion rates (Figures 12A and 12B). Overall, the reduced fat and lean mass loss correlated with more activity in the mice.

Claims

1. A combination comprising an ActRII receptor antibody and tirzepatide, wherein the ActRII receptor antibody comprises a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3), and a variable light chain comprising the CDR amino acid sequences of SEQ ID NO: 4 (CDRL1), SEQ ID NO: 5 (CDRL2), and SEQ ID NO: 6 (CDRL3).

2. 2. The combination of claim 1, wherein the ActRII receptor antibody comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO:7, or an amino acid sequence having at least 90% sequence identity thereto, and a variable light chain comprising the amino acid sequence of SEQ ID NO:8, or an amino acid sequence having at least 90% sequence identity thereto.

3. 2. The combination of claim 1, wherein the ActRII receptor antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 90% sequence identity thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 90% sequence identity thereto.

4. 2. The combination of claim 1, wherein the ActRII receptor antibody comprises a human IgGl Fc domain having an alteration relative to a human IgGl Fc domain selected from the group consisting of 259I, 252Y, 307Q, 308F, 428L, 434H, 434F, 434Y, 434A, 434M, and 434S, according to the EU numbering scheme.

5. 2. The combination of claim 1, wherein the ActRII receptor antibody comprises a human IgG1 Fc domain having an alteration relative to a human IgG1 Fc domain selected from M428L and / or N434S, according to the EU numbering scheme.

6. The combination of claim 1 , wherein the antibody is specific for ActRIIA and ActRIIB.

7. A pharmaceutical composition comprising the combination of claim 1 and a pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising a combination of an ActRII receptor antibody and tirzepatide, wherein the ActRII receptor antibody comprises a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 (CDRH3), and a variable light chain comprising the CDR amino acid sequences of SEQ ID NO: 4 (CDRL1), SEQ ID NO: 5 (CDRL2), and SEQ ID NO: 6 (CDRL3).

9. The pharmaceutical composition of claim 8, wherein the ActRII receptor antibody comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 90% sequence identity thereto, and a variable light chain comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 90% sequence identity thereto.

10. The pharmaceutical composition of claim 8, wherein the ActRII receptor antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 90% sequence identity thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 90% sequence identity thereto.

11. A pharmaceutical composition as described in claim 7, which is used in a method for treating a metabolic disorder.

12. A pharmaceutical composition comprising an ActRII antibody for use in a method for treating a metabolic disorder, said method comprising combination with tirzepatide, said ActRII receptor antibody comprising a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO:1 (CDRH1), SEQ ID NO:2 (CDRH2), and SEQ ID NO:3 (CDRH3), and a variable light chain comprising the CDR amino acid sequences of SEQ ID NO:4 (CDRL1), SEQ ID NO:5 (CDRL2), and SEQ ID NO:6 (CDRL3).

13. A pharmaceutical composition comprising tirzepatide for use in a method for treating a metabolic disorder, said method comprising combination with an ActRII antibody, said ActRII receptor antibody comprising a variable heavy chain comprising the CDR amino acid sequences of SEQ ID NO:1 (CDRH1), SEQ ID NO:2 (CDRH2), and SEQ ID NO:3 (CDRH3), and a variable light chain comprising the CDR amino acid sequences of SEQ ID NO:4 (CDRL1), SEQ ID NO:5 (CDRL2), and SEQ ID NO:6 (CDRL3).

14. The pharmaceutical composition of claim 11, wherein the metabolic disorder is selected from the group consisting of obesity, type I diabetes, type II diabetes, metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, Prader-Willi syndrome, and monogenic disorders associated with obesity.

15. The pharmaceutical composition of claim 14, wherein the treatment is useful for treating obesity-related comorbid conditions, the conditions being selected from the group consisting of impaired glucose tolerance, prediabetes, insulin resistance, elevated triglycerides, physical disorders associated with overweight, osteoporosis, renal disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

16. The pharmaceutical composition described in claim 11, wherein the subject has a body mass index (BMI) of 30 or greater.

17. The pharmaceutical composition described in claim 11, wherein the subject has a BMI of 27 or greater and one or more obesity-related comorbidities.

18. The pharmaceutical composition of claim 11, wherein the ActRII receptor antibody and / or tirzepatide are administered subcutaneously.

19. The pharmaceutical composition of claim 11, wherein the ActRII receptor antibody is administered prior to tirzepatide.

20. The pharmaceutical composition of claim 11, wherein tirzepatide is administered prior to the ActRII receptor antibody.

21. The pharmaceutical composition of claim 11, wherein the ActRII receptor antibody and the tirzepatide are administered simultaneously.

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