ActRII Antibody Therapy

Abstract

Provided herein is an ActRII antibody dosing regimen for the treatment of metabolic disorders, including obesity. In some embodiments, the dosing regimen is preceded by administration of a loading dose of the ActRII antibody, which can further optimize the efficacy of treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 301,011, filed January 19, 2022, and U.S. Provisional Patent Application No. 63 / 373,676, filed August 26, 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_008_02WO_SeqList_ST26.xml, size: 10,565 bytes, created on: January 18, 2023) are incorporated herein by reference in their entirety. [Background technology]

[0003] Treatment of metabolic disorders such as obesity remains elusive because the regulation of metabolism and fat storage involves complex biological feedback systems.Even if a safe and effective drug is identified as capable of treating metabolic disorders, the administration paradigm may be further optimized for effective and efficient administration in overweight and obese patient populations, and in populations that often exhibit obesity-related comorbidities that require long-term treatment.Therefore, there is a need for an optimized administration paradigm for the treatment of metabolic disorders, including obesity, and accordingly, is provided herein. Summary of the Invention

[0004] The present disclosure relates to the dosage and administration of ActRII pathway agents, such as ActRII antibodies, for the treatment of metabolic disorders. Treatment with ActRII antibodies can improve metabolic dysfunction, including reducing body fat mass, increasing lean mass, and / or improving glycemic control. In some embodiments, ActRII antibody treatments are provided herein that include ActRII antibody dosing regimens for the treatment of metabolic disorders. In some embodiments, the ActRII antibody treatments include one or more loading doses of ActRII antibodies administered prior to the initiation of the ActRII antibody dosing regimen.

[0005] In one aspect, provided herein is an ActRII antibody dosing regimen that includes administering an ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg about once every 8 weeks to about once every 16 weeks, wherein the ActRII antibody dosing regimen is administered intravenously. In some embodiments, the ActRII antibody dosing regimen follows administration of an ActRII antibody loading dose.

[0006] In some embodiments, the ActRII antibody dosing regimen and / or ActRII antibody loading dose comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 1-6. In some embodiments, the ActRII antibody dosing regimen and / or ActRII antibody loading dose comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and comprising an amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto. In some embodiments, the ActRII antibody dosing regimen and / or ActRII antibody loading dose comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and comprising an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto. In some embodiments, the ActRII antibody dosing regimen and / or ActRII antibody loading dose comprises administration of an ActRII antibody specific for ActRIIA and ActRIIB.

[0007] In some embodiments, the ActRII antibody therapy provided herein treats a metabolic disorder selected from the group consisting of obesity, diabetes, metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and monogenic disorders associated with obesity. In some embodiments, the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity resulting from a mutation 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B. In some embodiments, the metabolic disorder is Prader-Willi syndrome. In some embodiments, the diabetes is type I diabetes or type II diabetes.

[0008] In some embodiments, the ActRII antibody therapy treats an obesity-related comorbidity selected from the group consisting of impaired glucose tolerance, prediabetes, insulin resistance, high triglycerides, physical disorders associated with overweight, osteoporosis, renal disease, cardiometabolic disease, non-alcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

[0009] In some embodiments, ActRII antibody treatment reduces body weight in a subject. In some embodiments, ActRII antibody treatment reduces fat mass in a subject. In some embodiments, ActRII antibody treatment increases lean mass in a subject. In some embodiments, ActRII antibody treatment reduces fat mass and increases lean mass in a subject. In some embodiments, ActRII antibody treatment reduces fat mass and preserves lean mass in a subject. In some embodiments, ActRII antibody treatment reduces waist circumference in a subject. In some embodiments, ActRII antibody treatment reduces hepatic and / or non-hepatic fat mass in a subject. In some embodiments, ActRII antibody treatment improves glycemic control in a subject.

[0010] In some embodiments, the efficacy of ActRII antibody treatment can be assessed by the following measures: weight, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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 physical performance battery (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, and / or urinary biomarkers; 2) (HOMA2), and physical activity monitoring via actigraphy.

[0011] In some embodiments, the efficacy of ActRII antibody treatment is assessed by measuring the C trough In some embodiments, the C of a sample from a subject is measured. trough is the desired "C trough In some embodiments, the desired "C" of the ActRII antibody treatment is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75%. trough " is 10 μg / ml. In some embodiments, the subject of ActRII antibody treatment is a human.

[0012] In another aspect, provided herein is an ActRII antibody treatment comprising an ActRII antibody loading dose followed by an ActRII antibody dosing regimen.

[0013] In some embodiments, the ActRII antibody loading dose is about 3 mg / kg to about 50 mg / kg. In some embodiments, the ActRII antibody dosing regimen is initiated about 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, or about 5 weeks after the loading dose of the ActRII antibody. In some embodiments, the ActRII antibody dosing regimen includes administration of the ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg. In some embodiments, the ActRII antibody dosing regimen includes administration of the ActRII antibody about every 4 weeks, about every 8 weeks, about every 12 weeks, or about every 16 weeks. In some embodiments, the ActRII antibody of the ActRII antibody loading dose and dosing regimen is administered intravenously.

[0014] In some embodiments, the loading dose of the ActRII antibody and / or the ActRII antibody dosing regimen comprises the amino acid sequence of SEQ ID NO: 1-6. In some embodiments, the loading dose of the ActRII antibody and / or the ActRII antibody dosing regimen comprises the amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and the amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto. In some embodiments, the loading dose of the ActRII antibody and / or the ActRII antibody dosing regimen comprises the amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and the amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto. In some embodiments, the loading dose of the ActRII antibody and / or the ActRII antibody dosing regimen is specific for ActRIIA and ActRIIB.

[0015] 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, and monogenic disorders associated with obesity. In some embodiments, the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity resulting from a mutation 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B. In some embodiments, the metabolic disorder is Prader-Willi syndrome. In some embodiments, the diabetes is type I diabetes or type II diabetes.

[0016] In some embodiments, the ActRII antibody therapy treats an obesity-related comorbidity selected from the group consisting of impaired glucose tolerance, prediabetes, insulin resistance, high triglycerides, physical disorders associated with overweight, osteoporosis, renal disease, cardiometabolic disease, non-alcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

[0017] In some embodiments, ActRII antibody treatment reduces body weight in a subject. In some embodiments, ActRII antibody treatment reduces fat mass in a subject. In some embodiments, ActRII antibody treatment increases lean mass in a subject. In some embodiments, ActRII antibody treatment reduces fat mass and increases lean mass in a subject. In some embodiments, ActRII antibody treatment reduces fat mass and preserves lean mass in a subject. In some embodiments, ActRII antibody treatment reduces waist circumference in a subject. In some embodiments, ActRII antibody treatment reduces hepatic and / or non-hepatic fat mass in a subject. In some embodiments, ActRII antibody treatment improves glycemic control in a subject.

[0018] In some embodiments, the efficacy of ActRII antibody treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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.

[0019] In some embodiments, the efficacy of ActRII antibody treatment is assessed by measuring the C trough In some embodiments, the C of a sample from a subject is measured. trough is the desired "C trough In some embodiments, the desired "C" of the ActRII antibody treatment is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75%. trough " is 10 μg / ml. In some embodiments, the subject of ActRII antibody treatment is a human. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 is a plot of kilograms of fat mass (kg) versus lean body mass (kg) for individual patients in the seven clinical trials evaluated, as described in the Examples. [Diagram 2] 1 is a plot of age (years) versus lean body mass (kg) for individual patients in the same seven clinical trials evaluated. [Diagram 3] A plot of age (years) versus fat mass (kg) for individual patients in the same seven clinical trials evaluated. [Figure 4] A plot of age (years) versus weight (kg) for individual patients in the same seven clinical trials evaluated. [Diagram 5] FIG. 1 is a pair of graphs showing (left) bimagrumab treated patients where there was an association between increased lean body mass (LBM) and decreased fat body mass (FBM) and (right) the placebo group where there was no association between changes in FBM and LBM. [Figure 6] FIG. 1 is a schematic diagram of the pharmacokinetic and pharmacodynamic (PK / PD) bimagrumab dosing model. [Figure 7] 1 is a pair of graphs showing observed versus model-predicted bimagrumab exposure (PK) concentrations for the clinical trial population (left) and individual patients (right). [Figure 8]FIG. 8 is a pair of graphs showing observed versus predicted bimagrumab exposure (PK) concentrations from FIG. 7 on a log-log scale for the clinical trial population (left) and for individual patients (right). [Figure 9] FIG. 13 is a plot showing predicted median and observed median with 90% confidence intervals (areas) of bimagrumab concentration exposure (PK) over time across all studies. [Figure 10] Three graphs by patient weight (in kilograms from minimum on the left to maximum on the right) showing predicted and observed medians with 90% confidence intervals (areas) of bimagrumab concentration exposure (PK) over time. [Figure 11] 1 is a pair of graphs showing observed versus predicted fat body mass (FBM) for a clinical trial population (left) and for individual patients (right). [Figure 12] FIG. 1 shows three graphs showing predicted and observed medians with 90% confidence intervals (areas) of fat body mass (FBM) by weight group (in kilograms from minimum on the left to maximum on the right). [Figure 13] 1 is a pair of graphs showing observed vs. predicted lean body mass (LBM) for a clinical trial population (left) and for individual patients (right). [Figure 14] FIG. 1 shows three graphs showing predicted and observed medians with 90% confidence intervals (areas) of lean body mass (LBM) by weight group (in kilograms from minimum on the left to maximum on the right). [Figure 15] 1 is a plot showing predicted median bimagrumab serum concentrations (% of baseline) for different bimagrumab dosing regimens. [Figure 16] 1 is a plot showing the predicted median effect (% relative to baseline) on FBM and LBM of different bimagrumab dosing regimens. [Figure 17] 1 is a plot showing the predicted median effect (% relative to baseline) on combined FBM and LBM for different bimagrumab dosing regimens. [Figure 18]1 is a plot showing predicted median bimagrumab serum concentrations (% of baseline) for different bimagrumab dosing regimens with and without a loading dose. The dosing regimen with a loading dose is initiated 4 weeks after administration of the loading dose (week 4). [Figure 19] 1 is a plot showing the predicted median effect (% of baseline) on FBM and LBM of different bimagrumab dosing regimens with and without a loading dose. Dosing regimens with a loading dose are initiated 4 weeks after administration of the loading dose (week 4). [Figure 20] 1 is a plot showing the predicted median effect (% relative to baseline) on combined FBM and LBM for different bimagrumab dosing regimens. [Figure 21] Box plots showing predicted responses (% of baseline) for fat mass (FBM) and lean mass (LBM) for different bimagrumab dosing regimens with and without a loading dose at weeks 24, 36, and 48. Dosing regimens with a loading dose will begin 4 weeks after administration of the loading dose (week 4). [Figure 22] 2A-2C are two graphs showing the effect of body weight on the concentration-time profile of bimagrumab antibody treatment that includes a loading dose at week 0 prior to a dosing regimen starting at week 4. [Diagram 23] 2A-2C are two graphs showing the effect of body weight on fat mass (FBM)-time profile of bimagrumab antibody treatment including a loading dose at week 0, prior to a dosing regimen starting at week 4. [Figure 24] 1 is a graph showing predicted fat mass loss (FBM half-life) versus bimagrumab serum concentration. The loading dose is predicted to help maintain serum concentrations of the ActRII antibody above saturation concentrations of the ActRII receptor. [Diagram 25] FIG. 1 is a schematic diagram of an exemplary clinical trial designed to evaluate the efficacy of bimagrumab antibody treatment administered every 12 weeks, including a loading dose at week 0, followed by a dosing regimen starting at week 4. Detailed Description of the Invention

[0021] Provided herein are dosing regimens of ActRII pathway agents, e.g., ActRII antibodies, for the treatment of metabolic disorders. Treatment with an ActRII antibody can improve metabolic dysfunction, including reducing body fat mass, increasing lean mass, and / or improving glycemic control. In some embodiments, the ActRII antibody treatment comprises a dosing regimen in which the ActRII antibody is administered at a dose of about 3-50 mg / kg, e.g., about 30 mg / kg, about once every 8 weeks to about once every 16 weeks, e.g., about once every 12 weeks, and the dose is administered intravenously. In some embodiments, the ActRII antibody treatment comprises the use of one or more loading doses in addition to the dosing regimen.

[0022] I. Definition Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill 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.

[0023] It should be noted that as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents 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.

[0024] 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 to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that is within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of a stated reference value (except where such number would exceed 100% of possible values), unless otherwise stated or clear from the context.

[0025] Where a range of values ​​is provided, unless the context clearly dictates otherwise, 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. The upper and lower limits of these smaller ranges are also independently encompassed within the disclosure as being within the smaller ranges, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0026] 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.

[0027] As used herein, the terms "identity" and "identical" refer to the percentage of exact matching residues in an alignment of a sequence of interest to a reference sequence, such as an alignment generated by the BLAST algorithm, with respect to a polypeptide sequence of interest. Unless otherwise specified, identity is calculated over the full length of the reference sequence. Thus, when a reference sequence (as a query sequence) is aligned to a sequence of interest (as a subject sequence), a sequence of interest "shares at least x% identity" with a reference sequence if at least x% (truncated) of the residues in the subject sequence are aligned to exactly match the corresponding residues in the query sequence (the denominator is the full length of the reference sequence plus the length of any gaps inserted in the reference sequence by the alignment of the reference sequence to the subject sequence). If the subject sequence has variable positions (e.g., residues marked with X), alignment to any residue in the query sequence is counted as a match. Sequence alignment can be performed using the NCBI Blast service (BLAST+ version 2.12.0) or another program that produces the same results.

[0028] As used herein, "antibody" includes reference to an immunoglobulin molecule 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, and single-chain antibody fragments (scAb). The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies.

[0029] 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 predisposed to developing the disease but not yet diagnosed as having developed it, (b) inhibiting or delaying the onset or progression of the disease, or (c) relieving 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 undesirable clinical symptoms in 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 treatment is administered during the symptomatic stage of the disease, and in some embodiments after the symptomatic stage of the disease.

[0030] As used herein, the term "dose" refers to the amount of a therapeutic agent administered to a subject to achieve a therapeutic objective.

[0031] The term "loading dose" refers to one or more doses of a therapeutic agent that are administered in addition to a dosing regimen. As used herein, a "loading dose" can refer to one or more doses of a therapeutic agent that are at the same concentration, lower concentration, or higher concentration than the dose of the therapeutic agent that is administered as part of the dosing regimen. In some embodiments, the loading dose is administered before the start of a round of the dosing regimen.

[0032] As used herein, the term "dosage" refers to the amount, number, and frequency of administration over the course of treatment.

[0033] As used herein, the term "dosing regimen" refers to repeated periodic administration of a therapeutic agent. As used herein, a dosing regimen does not include a loading dose, which in some embodiments may be administered additionally, for example, prior to a round of the dosing regimen.

[0034] As used herein, the term "antibody therapy" or "ActRII therapy" refers to a therapy that includes a dosing regimen. In some embodiments, the term refers to a dosing regimen and one or more loading doses.

[0035] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to any subject for which treatment 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).

[0036] As used herein, metabolic disorders refer to disorders affecting the dysregulation of mammalian metabolism, including, but not limited to, obesity, diabetes (type I and type II), metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and obesity associated with multiple and monogenic disorders. Single gene disorders associated with obesity in humans can include, but are not limited to, Bardet-Biedl syndrome and 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B, or combinations thereof. Metabolic disorders can also be associated with multiple gene disorders, such as Prader-Willi syndrome.

[0037] As used herein, Body Mass Index or "BMI" refers to the unit of body weight in kilograms (kg) divided by the unit of body mass per square meter (m 2 ) divided by height in meters and rounded to one decimal place. As used herein, "obesity" in adult humans is defined as a body mass index greater than or equal to 30 kg / m 2 "Obesity" in human youth is defined as a BMI equal to or greater than the age- and sex-specific 95th percentile of the CDC 2000 growth charts. The term "overweight" is defined as a BMI equal to or greater than 25 and equal to or less than 30.

[0038] The terms "obesity-related comorbidities" and "obesity-related conditions" 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 risk of death in a subject. Obesity-related comorbidities 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, cardiometabolic disease, cardiometabolic syndrome, nonalcoholic fatty liver disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory disorders, cancer, reduced quality of life, mental illnesses such as clinical depression, anxiety, and other mental disorders, and physical pain and difficulties with physical function. Obesity-related cancers include, but are not limited to, gastrointestinal cancer, including but not limited to adenocarcinoma of the esophagus, stomach, colon, and rectum, breast cancer in postmenopausal women, uterine cancer, gallbladder cancer, kidney cancer, liver cancer, ovarian cancer, pancreatic cancer, thyroid cancer, meningioma, and multiple myeloma.

[0039] "Lean mass" is defined as the subject's total body weight minus the subject's fat mass. Lean mass and fat mass may be measured, for example, by bioelectrical impedance analysis (BIA) or dual energy x-ray absorptiometry (DXA).

[0040] II. ActRII pathway modulators ActRII 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 Smad-dependent pathways. For example, it is believed that the formation of skeletal muscle can be induced by inhibiting or preventing myostatin from binding to ActRIIB via ActRII antibodies. Regulation of activin receptor II A (ActRIIA) also plays a role in regulating muscle growth (Morvan et al. 2017).

[0041] Exemplary ActRII antibodies that bind to ActRIIA and ActRIIB have been shown in human clinical trials to not only increase lean muscle mass, but also reduce body fat mass and improve glycemic control (WO2010 / 125003A1, WO2018 / 116201A1, and Heymsfield et al. 2021;4(1):e2033457, JAMA, the contents of which are incorporated in their entirety). Exemplary ActRII antibodies that may be used in some embodiments include the isolated, structurally characterized, human recombinant antibodies described in WO2010 / 125003A1.

[0042] In some embodiments, an exemplary antibody of the disclosure comprises the sequence of bimagrumab (BYM338). The following table provides the relevant CDR, VH, VL, HC, and LC amino acid sequences for bimagrumab. [Table 1] [Table 2]

[0043] In some embodiments, an exemplary ActRII 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).

[0044] In some embodiments, an exemplary ActRII 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).

[0045] In some embodiments, an exemplary ActRII 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), 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).

[0046] In some embodiments, an exemplary ActRII antibody of the 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 a variable light chain comprising an amino acid sequence of SEQ ID NO:8, 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.

[0047] In some embodiments, an exemplary ActRII antibody of the 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 a light chain comprising an amino acid sequence of SEQ ID NO: 10, 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.

[0048] In some embodiments, the ActRII antibody binds to ActRIIB with a KD of 100 nM or less, 10 nM or less, 1 nM or less. In exemplary embodiments, the ActRII 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 antibody binds to ActRIIB with an affinity of 10-20 pM.

[0049] In some embodiments, the ActRII antibody binds to ActRIIB with an affinity that is 5-fold, 10-fold, 50-fold, or even 100-fold higher than ActRIIA. In some embodiments, the ActRII antibody binds to ActRIIA with an affinity of 100 pM or greater (i.e., 250 pM, 500 pM, 1 nM, 5 nM, or greater).

[0050] Other ActRII pathway agents In other embodiments, the treatments described herein include agents that bind to ActRII receptor ligands, for example, directly bind 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 soluble extracellular portions of ActRIIB or ActRIIA that can act as "ligand sinks" optionally further stabilized with Fc. In some embodiments, the treatments described herein include bispecific antibodies that can bind to both activin and myostatin. Thus, in some embodiments, a method of treating a metabolic disorder of the present disclosure is provided herein, comprising administering to a subject in need thereof an ActrII pathway agent (other than an ActRII antibody), wherein the agent is selected from the group consisting of a myostatin inhibitor, an activin inhibitor, or a soluble portion of the ActRII receptor or a bispecific antibody.

[0051] III.ActRII antibody treatment An ActRII antibody (or other ActRII pathway agent) may be administered to a subject in need thereof to treat a metabolic disorder. An ActRII antibody treatment of the present disclosure may include an ActRII antibody dosing regimen. In some embodiments, an ActRII antibody treatment may include one or more optional loading doses of an ActRII antibody (or other ActRII pathway agent) in addition to a dosing regimen. In an exemplary embodiment, an ActRII 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) is administered in a dosing regimen. In an exemplary embodiment, an ActRII 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) is administered in a loading dose and dosing regimen.

[0052] In some embodiments, the ActRII antibody treatments provided herein include a dosing regimen that includes administering an ActRII antibody intravenously to a subject in need thereof at a dose of about 3-50 mg / kg, e.g., about 30 mg / kg, about once every 8 weeks to about once every 16 weeks, e.g., about once every 12 weeks. In some embodiments, the dosing regimen includes administering an ActRII antibody intravenously to a subject in need thereof at a dose of about 30 mg / kg about every 12 weeks.

[0053] In other embodiments of the ActRII antibody treatments contemplated herein, the ActRII antibody is administered to a subject in need thereof at a dose of about 200 mg to about 400 mg.

[0054] As provided herein, ActRII antibody therapy can be administered by any route, for example, in exemplary embodiments, the ActRII antibody can be administered intravenously or subcutaneously.

[0055] loading dose In some embodiments, administering a loading dose in addition to a dosing regimen may improve the outcome of ActRII antibody treatment.Without being bound by theory, it is believed that administering a loading dose may maintain the level of ActRII antibody in the serum of subject for a long period of time.Therefore, in some embodiments, a loading dose is provided herein.

[0056] The loading dose maintains the serum concentration of the ActRII antibody at or above the saturation concentration of the ActRII receptor. In some embodiments, about 10 μg / ml of the ActRII antibody is a concentration sufficient to saturate ActRII receptor signaling in a subject.

[0057] In some embodiments, "C trough " refers to the lowest serum concentration of an ActRII antibody during a subject's treatment, and in most cases refers to the serum level of an ActRII antibody prior to the next dose. In some embodiments, trough is approximately the same concentration as the ActRII receptor saturation concentration. trough In some embodiments, C is about 3 μg / ml to about 30 μg / ml. trough In some embodiments, the loading dose is about 3 to about 30 μg / ml. trough In some embodiments, the loading dose is trough in the subject's serum at about 4 μg / ml, at about 5 μg / ml, at about 6 μg / ml, at about 7 μg / ml, at about 8 μg / ml, at about 9 μg / ml, at about 10 μg / ml, at about 11 μg / ml, at about 12 μg / ml, at about 13 μg / ml, at about 14 μg / ml, at about 15 μg / ml, at about 16 μg / ml, at about 17 μg / ml In some embodiments, the desired C is maintained at about 18 μg / ml, about 19 μg / ml, about 20 μg / ml, about 21 μg / ml, about 22 μg / ml, about 23 μg / ml, about 24 μg / ml, about 25 μg / ml, about 26 μg / ml, about 27 μg / ml, about 28 μg / ml, about 29 μg / ml, or about 30 μg / ml to measure the efficacy of bimagrumab treatment. trough In some embodiments, the loading dose is selected to be about 10 μg / ml Ctrough maintain.

[0058] In some embodiments, the loading dose reduces the desired C compared to a dosing regimen without a loading dose. trough Thus, in some embodiments, a loading dose is included in the treatment, which is believed to maximize the efficacy and safety of ActRII antibody treatment.

[0059] In some embodiments, one or more loading doses of an ActRII antibody are administered to a subject in need thereof on day 0 or week 0 prior to the initiation of a subsequent dosing regimen. In some embodiments, one or more loading doses of an ActRII 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 administration of an ActRII antibody dosing regimen. In an exemplary embodiment, a loading dose is administered about 4 weeks prior to the initiation of the dosing regimen.

[0060] In some embodiments, the second administration of 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 dosing regimen. In some embodiments, the subject is administered one or more loading doses, followed by the dosing regimen, and then a second round of treatment, such as a second initiation of one or more loading doses, followed by a repeat dosing regimen. Similarly, the treatment may further include a third set of one or more loading doses, followed by a third round of the dosing regimen, and so on. In some embodiments, the one or more loading doses are administered periodically or periodically in addition to the dosing regimen. In an exemplary embodiment, the loading dose is first administered about 4 weeks before the start of the dosing regimen, and is administered about once a year thereafter in addition to the dosing regimen.

[0061] In some embodiments, a loading dose is administered prior to an ActRII antibody dosing regimen, which includes administration of an ActRII antibody at a dose of about 3 to 50 mg / kg, e.g., about 30 mg / kg, about once every 8 weeks to about once every 16 weeks, for example, about once every 12 weeks, which dose is administered intravenously.

[0062] In some embodiments, the loading dose is a dose of ActRII antibody at the same concentration, a lower concentration, or a higher concentration than the dose of ActRII antibody administered in the dosing regimen. Thus, the loading dose can be about 3 mg / kg of subject's body weight to about 50 mg / kg of subject's body weight, and all amounts therebetween. In exemplary embodiments, a loading dose of about 3 mg / kg of subject's body weight to about 50 mg / kg of subject's body weight is administered intravenously. In some exemplary embodiments, a loading dose of about 30 mg / kg of ActRII antibody is administered to the subject about 4 weeks prior to the start of the dosing regimen, and is administered intravenously.

[0063] In some embodiments, a loading dose of the ActRII antibody is administered to a subject in need thereof, e.g., intravenously, 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, the dose is 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, 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, and in some embodiments, at a dose of about 33 mg / kg. In 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, and in some embodiments, at a dose of about 44 mg / kg.In some embodiments, the ActRII antibody 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. In an exemplary embodiment, the loading dose of the ActRII antibody is about 10 mg / kg of subject body weight. In another exemplary embodiment, the loading dose of the ActRII antibody is about 30 mg / kg of subject body weight and is administered intravenously.

[0064] In some exemplary embodiments, a loading dose of about 3 to 50 mg / kg is administered intravenously about 0 to about 12 weeks prior to initiation of an ActRII antibody dosing regimen, the dosing regimen comprising administration of an ActrII antibody at a dose of about 3 mg / kg to about 50 mg / kg (e.g., about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, or about 50 mg / kg) about once every 8 weeks to about once every 16 weeks, and the ActRII antibody dosing regimen is administered intravenously. In some exemplary embodiments, a loading dose of about 30 mg / kg is administered intravenously about 4 weeks prior to initiation of an ActRII antibody dosing regimen, the dosing regimen comprising administration of an ActrII antibody at a dose of about 30 mg / kg about once every 12 weeks, and the ActRII antibody dosing regimen is administered intravenously.

[0065] In other exemplary embodiments, the loading dose of the ActRII antibody may be about 200 mg to about 400 mg per dose, may not be determined by the subject's body weight, or may be fixed at a dose applicable over a range of the subject's body weight, and may be administered subcutaneously. In some exemplary embodiments, the loading dose of the ActRII antibody is about 200 mg to about 400 mg per dose and is administered subcutaneously. In some exemplary embodiments, the loading dose of the ActRII antibody is about 200 mg per dose. In some exemplary embodiments, the loading dose of the ActRII antibody is about 250 mg per dose. In some exemplary embodiments, the loading dose of the ActRII antibody is about 300 mg per dose. In some exemplary embodiments, the loading dose of the ActRII antibody is about 350 mg per dose. In some exemplary embodiments, the loading dose of the ActRII antibody is about 400 mg per dose. In some exemplary embodiments, the loading dose of the ActRII antibody is about 300 mg per dose and is administered subcutaneously.

[0066] Medication Regimen The dosing regimen contemplated herein is regular repeated dosing of an ActRII antibody (or other ActRII pathway agent).

[0067] In some exemplary embodiments, the dosing regimen may be administered to a subject in need thereof at a dose of about 3 mg / kg to about 50 mg / kg. In some exemplary embodiments, the dosing regimen may be administered intravenously to a subject in need thereof at a dose of about 3 mg / kg to about 50 mg / kg.

[0068] In some embodiments, the dosing regimen comprises administering 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 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. and 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. / 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 ActRII antibody 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. In an exemplary embodiment, the ActRII antibody in the dosing regimen is administered to a subject in need thereof at a dose of 10 mg / kg. In another exemplary embodiment, the ActRII antibody in the dosing regimen is administered to a subject in need thereof at a dose of 30 mg / kg.

[0069] In some embodiments, the ActRII antibody is administered to a subject in need thereof in a dosing regimen two, three, four, five or more times. In some embodiments, the ActRII antibody in a dosing regimen is administered about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, about every 13 weeks, about every 14 weeks, about every 15 weeks, or about every 16 weeks. In some embodiments, the ActRII antibody is administered every quarter of a year. In some embodiments, the ActRII antibody in a dosing regimen is administered intravenously at a dose of about 3 mg / kg to about 50 mg / kg about every 8 to about 16 weeks. In some embodiments, the ActRII antibody is administered intravenously at a dose of about 30 mg / kg about every 12 weeks.

[0070] In some embodiments, the ActRII antibody of the dosing regimen is administered intravenously at a dose of about 30 mg / kg about every 12 weeks, optionally followed by administration of a loading dose.

[0071] In some embodiments, the ActRII antibody of the dosing regimen is administered intravenously at a dose of about 3 to about 50 mg / kg about every 12 weeks, optionally after administration of a loading dose, optionally about 4 weeks prior to initiation of the dosing regimen, and optionally about annually thereafter. In some embodiments, the ActRII antibody of the dosing regimen is administered intravenously at a dose of about 30 mg / kg about every 12 weeks, optionally after administration of a loading dose, optionally about 4 weeks prior to initiation of the dosing regimen, and optionally about annually thereafter.

[0072] In some exemplary embodiments, a loading dose of about 3-50 mg / kg is administered intravenously about 0 to about 12 weeks prior to initiation of an ActRII antibody dosing regimen, the dosing regimen comprising administration of an ActrII antibody at a dose of about 3 mg / kg to about 50 mg / kg about once every 8 weeks to about once every 16 weeks, and the ActRII antibody dosing regimen is administered intravenously. In some exemplary embodiments, a loading dose of about 30 mg / kg is administered intravenously about 4 weeks prior to initiation of an ActRII antibody dosing regimen, the dosing regimen comprising administration of an ActrII antibody at a dose of about 30 mg / kg about once every 12 weeks, and the ActRII antibody dosing regimen is administered intravenously.

[0073] In some embodiments, the ActRII 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 antibody is administered at a dosage regimen of about 200 to about 400 mg, e.g., about 300 mg, once per week, twice, three or more times per week, or once every two weeks. In some embodiments, the ActRII antibody is administered at a dosage regimen of about 300 mg once per week. In some embodiments, the ActRII antibody is administered subcutaneously at a dosage regimen of about 300 mg once per week.

[0074] In other exemplary embodiments, the ActRII antibody in the dosing regimen is administered at a weight of about 200 mg to about 400 mg per dose. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered subcutaneously at a weight of about 200 mg to about 400 mg per dose. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered at a weight of about 200 mg. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered at a weight of about 250 mg. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered at a weight of about 300 mg. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered at a weight of about 350 mg. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered at a weight of about 400 mg. In some exemplary embodiments, the ActRII antibody in the dosing regimen is administered subcutaneously at a weight of about 300 mg.

[0075] In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 200 mg. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 200 mg once a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 200 mg twice a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 200 mg three times a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 200 mg every two weeks. In some embodiments, the ActRII antibody of the dosing regimen is administered subcutaneously at a dose of about 200 mg.

[0076] In an exemplary embodiment, the ActRII antibody of the dosing regimen is administered at a dose of about 300 mg. In an exemplary embodiment, the ActRII antibody of the dosing regimen is administered at a dose of about 300 mg once a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 300 mg twice a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of 300 mg three times a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 300 mg every two weeks. In an exemplary embodiment, the ActRII antibody of the dosing regimen is administered subcutaneously at a dose of about 300 mg. In an exemplary embodiment, the ActRII antibody of the dosing regimen is administered subcutaneously at a dose of about 300 mg once a week.

[0077] In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 400 mg. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 400 mg once a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 400 mg twice a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of 400 mg three times a week. In some embodiments, the ActRII antibody of the dosing regimen is administered at a dose of about 400 mg every two weeks. In some embodiments, the ActRII antibody of the dosing regimen is administered subcutaneously at a dose of about 400 mg once a week.

[0078] Route of administration In some embodiments, the loading dose and / or dosing regimen of the ActRII antibody may be delivered orally, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, intravaginally, intrarectally, or intraocularly. In an exemplary embodiment, the loading dose and / or dosing regimen of the ActRII antibody is administered intravenously. In other exemplary embodiments, the loading dose and / or dosing regimen of the ActRII antibody is administered subcutaneously.

[0079] In some exemplary embodiments, the ActrII antibody is administered intravenously at a dose of about 3 mg / kg to about 50 mg / kg about once every 8 weeks to about once every 16 weeks.

[0080] In other exemplary embodiments, a loading dose of about 3 to about 50 mg / kg is administered intravenously about 0 to about 12 weeks prior to initiation of an ActRII antibody dosing regimen, the dosing regimen comprising administration of an ActrII antibody at a dose of about 3 mg / kg to about 50 mg / kg about once every 8 weeks to about once every 16 weeks, and the ActRII antibody dosing regimen is administered intravenously. In some exemplary embodiments, a loading dose of about 30 mg / kg is administered intravenously about 4 weeks prior to initiation of an ActRII antibody dosing regimen, the dosing regimen comprising administration of an ActrII antibody at a dose of about 30 mg / kg about once every 12 weeks, and the ActRII antibody dosing regimen is administered intravenously.

[0081] Subjects and Treatment As described herein, ActRII therapy is useful for treating metabolic disorders in subjects in need of such treatment, including, but not limited to, obesity, diabetes (type I and type II), metabolic syndrome, antipsychotic-associated obesity, glucocorticoid-induced obesity, hypothalamic obesity associated with craniopharyngioma, and multiple and monogenic disorders associated with obesity. Single gene disorders associated with obesity in humans can include, but are not limited to, Bardet-Biedl syndrome and 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B, or combinations thereof. Metabolic disorders can also be associated with multiple gene disorders, such as Prader-Willi syndrome.

[0082] In some embodiments, the ActRII antibody therapy treats an obesity-related disorder or condition, which may include, but is not limited to, one or more of impaired glucose tolerance, pre-diabetes, insulin resistance, high triglycerides, overweight-related physical disorders, osteoporosis, kidney disease, cardiometabolic disease, non-alcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

[0083] In some embodiments, reference to cardiometabolic disease includes cardiometabolic syndrome, including, but not limited to, insulin resistance, glucose intolerance, dyslipidemia, hypertension, and central obesity, hi some embodiments, cardiometabolic syndrome includes risk of or prior experience of coronary heart disease and ischemic stroke.

[0084] In an exemplary embodiment, the metabolic disorder is treated with an ActRII antibody dosing regimen described herein, and optionally a loading dose of the ActRII antibody. The ActRII antibody treatment described herein may include a dosing regimen and / or a loading dose of an ActRII 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, administered in some embodiments every 12 weeks at a dosage of 10 μg / ml. In other embodiments, the ActRII antibody treatment described herein may include a dosing regimen and / or a loading dose of an ActRII 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, administered intravenously in some embodiments at a dosage of about 30 μg / ml every 12 weeks. In other embodiments, ActRII antibody treatments described herein may include a dosing regimen and / or loading dose of an ActRII 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, in some embodiments administered weekly, e.g., subcutaneously, at a dosage of about 300 mg per dose. In some embodiments, one or more loading doses of an ActRII 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, are administered 4 weeks prior to the start of the dosing regimen, and optionally annually thereafter.

[0085] In some embodiments, the subject who needs the treatment described herein is an overweight subject.In some embodiments, the subject who needs the treatment described herein comprises the subject who has BMI 30 or more.In some embodiments, the subject who needs the treatment described herein comprises the subject who has BMI 27 or more with obesity-related comorbidities.

[0086] In some embodiments, the subject in need of treatment lacks glycemic control.

[0087] The subject can be of any age, including young. In some embodiments, the subject is over 40, over 45, over 50, over 60, or over 80 years old. In an exemplary embodiment, the subject is over 45 years old.

[0088] In some embodiments, the ActRII antibody treatment reduces body fat mass in a subject, hi some embodiments, the treatment reduces body fat mass in a subject by at least 5% (e.g., 5%-30%) over the treatment period.

[0089] In some embodiments, the ActRII antibody treatment increases lean mass in a subject, hi some embodiments, the treatment increases lean mass in a subject by at least 1% (e.g., 1%-10%) over the treatment period.

[0090] In some embodiments, ActRII antibody treatment reduces body fat mass and increases lean mass in a subject, hi some embodiments, treatment reduces body fat mass by at least 5% (e.g., 5%-30%) and increases lean mass by at least 1% (e.g., 1%-10%) in a subject over the treatment period.

[0091] In some embodiments, ActRII antibody treatment reduces body fat mass and preserves lean mass in a subject, hi some embodiments, treatment reduces body fat mass by at least 5% (e.g., 5%-30%) and preserves lean mass in a subject over the treatment period.

[0092] In some embodiments, the ActRII antibody treatment reduces body weight in a subject, hi 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.

[0093] In some embodiments, the ActRII antibody treatment reduces central obesity in a subject, hi some embodiments, the treatment reduces central obesity in a subject by at least 2% (e.g., 2% to 20%) over the treatment period.

[0094] In some embodiments, the ActRII antibody treatment reduces liver fat and / or non-hepatic visceral fat in a subject, hi some embodiments, the treatment reduces central obesity in a subject by at least 2% (e.g., 2%-20%) over the treatment period as assessed by magnetic resonance imaging (MRI).

[0095] In some embodiments, body fat mass in response to ActRII antibody treatment is measured by bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and / or waist circumference.

[0096] In some embodiments, ActRII antibody treatment improves glycemic control in a subject.

[0097] In some embodiments, glycemic control in response to ActRII antibody treatment is measured by glucose and insulin levels and the HOMA2 model is applied (www.dtu.ox.ac.uk / homacalculator / ).

[0098] In some embodiments, the efficacy of ActRII antibody treatment can be assessed by the following measures: weight, bioelectrical impedance analysis (BIA) of lean mass and / or fat mass, waist-to-hip ratio, waist-to-height ratio, dual x-ray absorptiometry (DXA) of lean mass and / or fat mass, magnetic resonance imaging (MRI) 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 (H The patient is assessed by about a 100%, about 90%, about 80%, about 75%, about 50%, or about 25% improvement in at least one of the following: (gbA1c) levels, hand muscle strength, glucose levels, insulin levels, Short Form Physical Performance Battery (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.

[0099] In some embodiments, the “C” in a sample from a subject undergoing treatment trough In some embodiments, the treatment can be performed by measuring the C of a sample from a subject to determine efficacy of the treatment. trough But the desired "C trough In some embodiments, the desired "C" is effective when the "C" is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the "C" in the desired range. trough In some embodiments, the desired "C trough " is approximately 10 μg / ml.

[0100] IV. Pharmaceutical Compositions In some embodiments, the ActRII antibody is in a pharmaceutical composition. In an exemplary embodiment, the composition comprises an ActRII 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). In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration.

[0101] In some embodiments, the composition includes an excipient or carrier, such as an aqueous carrier. A variety of aqueous carriers can be used, such as 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, such as disodium phosphate dihydrate, monosodium phosphate, sodium acetate, sodium chloride, potassium chloride, calcium chloride, hydrochloric acid, sodium hydroxide, L-histidine, L-histidine hydrochloride, 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 particular 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.

[0102] Exemplary embodiments Embodiment Set I: Embodiment I-1. A method of treating a metabolic disorder in a subject in need of such treatment, comprising administering to the subject an ActRII antibody loading dose followed by an ActRII antibody dosing regimen.

[0103] Embodiment I-2. A method of treating a metabolic disorder in a subject in need of treatment, the method comprising an ActRII antibody dosing regimen, wherein the ActRII antibody is administered to the subject about every 12 weeks.

[0104] The method of embodiment I-2, wherein the ActRII antibody dosing regimen follows administration of an ActRII antibody loading dose.

[0105] The method of embodiment I-1 or I-3, wherein the ActRII antibody loading dose is from about 3 mg / kg to about 50 mg / kg.

[0106] The method of embodiment I-1 or I-3, wherein the AcRII antibody loading dose is about 10 mg / kg.

[0107] The method of embodiment I-1 or I-3, wherein the AcRII antibody loading dose is about 30 mg / kg.

[0108] Embodiment I-7. A method according to any one of embodiments I-1 to I-6, wherein the ActRII antibody dosing regimen is initiated about 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, or about 5 weeks after the loading dose of the ActRII antibody.

[0109] Embodiment I-8. A method according to any one of embodiments I-1 to I-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg.

[0110] Embodiment I-9. The method of any one of embodiments I-1 to I-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 10 mg / kg.

[0111] Embodiment I-10. The method of any one of embodiments I-1 to I-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 30 mg / kg.

[0112] Embodiment I-11. A method according to any one of embodiments I-1 to I-10, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody about every 4 weeks, about every 8 weeks, about every 12 weeks, or about every 16 weeks.

[0113] The method of embodiment I-11, wherein the ActRII antibody dosing regimen comprises administration of the ActRII antibody about every 12 weeks.

[0114] The method of any one of embodiments I-1 or I-3 to I-12, wherein the ActRII antibody loading dose is administered intravenously.

[0115] Embodiment I-14. The method of any one of embodiments I-1 to I-12, wherein the ActRII antibody dosing regimen is administered intravenously.

[0116] The method of any one of embodiments I-1 or I-3 to I-12, wherein the ActRII antibody loading dose and the ActRII antibody dosing regimen are administered intravenously.

[0117] Embodiment I-16. The method of any one of embodiments I-1 or I-3 to I-12, wherein the loading dose of ActRII antibody comprises an amino acid sequence of SEQ ID NO: 1 to 6.

[0118] Embodiment I-17. The method of any one of embodiments I-1 or I-3 to I-12, wherein the loading dose of the ActRII antibody comprises an amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto.

[0119] Embodiment I-18. A method according to any one of embodiments I-1 or I-3 to I-12, wherein the loading dose of ActRII antibody comprises an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0120] Embodiment I-19. The method of any one of embodiments I-1 or I-3 to I-12, wherein the loading dose of ActRII antibody is specific for ActRIIA and ActRIIB.

[0121] Embodiment I-20. The method of any one of embodiments I-1 to I-19, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 1 to 6.

[0122] Embodiment I-21. A method according to any one of embodiments I-1 to I-19, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto.

[0123] Embodiment I-22. A method according to any one of embodiments I-1 to I-19, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0124] Embodiment I-23. A method according to any one of embodiments I-1 to I-19, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody specific for ActRIIA and ActRIIB.

[0125] Embodiment I-24. The method of any one of embodiments I-1 to I-23, wherein 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, and monogenic disorders associated with obesity.

[0126] The method of embodiment I-24, wherein the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

[0127] Embodiment I-26. The method of any one of embodiments I-1 to I-23, wherein the metabolic disorder is Prader-Willi syndrome.

[0128] Embodiment I-27. The method of embodiment I-24, wherein the diabetes is type I diabetes or type II diabetes.

[0129] Embodiment I-28. The method of embodiment I-24, wherein the method treats an obesity-related comorbidity selected from the group of impaired glucose tolerance, prediabetes, insulin resistance, high 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.

[0130] Embodiment I-29. The method of any one of embodiments I-1 to I-28, wherein the subject has a body mass index (BMI) of 30 or greater.

[0131] Embodiment I-30. The method of any one of embodiments I-1 to I-28, wherein the subject has a BMI of 27 or greater and one or more obesity-related comorbidities.

[0132] Embodiment I-31. The method of any one of embodiments I-1 to I-30, wherein the subject is overweight.

[0133] Embodiment I-32. The method of any one of embodiments I-1 to I-31, wherein the subject is 18 years of age or older.

[0134] The method of any one of embodiments I-1 to I-31, wherein the subject is 45 years of age or older.

[0135] Embodiment I-34. The method of any one of embodiments I-1 to I-31, wherein the subject is a child aged 0 to 17 years.

[0136] Embodiment I-35. The method of any one of embodiments I-1 to I-34, wherein the treatment reduces body weight in the subject.

[0137] Embodiment I-36. The method of any one of embodiments I-1 to I-35, wherein the treatment reduces body fat mass in the subject.

[0138] Embodiment I-37. The method of any one of embodiments I-1 to I-36, wherein the treatment increases lean mass in the subject.

[0139] Embodiment I-38. The method of any one of embodiments I-1 to I-37, wherein the treatment reduces fat mass and increases lean mass in the subject.

[0140] Embodiment I-39. The method of any one of embodiments I-1 to I-36, wherein the treatment reduces fat mass and preserves lean mass in the subject.

[0141] Embodiment I-40. The method of any one of embodiments I-1 to I-39, wherein treatment reduces the subject's waist circumference.

[0142] Embodiment I-41. The method of any one of embodiments I-1 to I-39, wherein the treatment reduces liver and / or non-hepatic fat mass in the subject.

[0143] Embodiment I-42. The method of any one of embodiments I-1 to I-40, wherein the treatment improves glycemic control in the subject.

[0144] Embodiment I-43. The method of any one of embodiments I-1 to I-41, wherein the efficacy of the treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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 (36) Health Survey (SF-36) assessment, Homeostasis Model Assessment 2 (HOMA2), and physical activity monitoring via actigraphy.

[0145] Embodiment I-44. The efficacy of the treatment is determined by the desired "C trough The method of any one of embodiments I-1 to I-41, wherein the .alpha.-to- ...

[0146] Embodiment I-45. Desired "C trough The method of embodiment I-44, wherein " is 10 μg / ml.

[0147] Embodiment I-46. The method of any one of embodiments I-1 to I-45, wherein the subject is a human.

[0148] Embodiment Set II: Embodiment II-1. A method for treating a metabolic disorder in a subject in need of such treatment, comprising administering to the subject an ActRII antibody loading dose followed by an ActRII antibody dosing regimen.

[0149] Embodiment II-2. A method for treating a metabolic disorder in a subject in need of treatment, the method comprising an ActRII antibody dosing regimen, wherein the ActRII antibody is administered to the subject about every 12 weeks.

[0150] The method of embodiment II-2, wherein the ActRII antibody dosing regimen follows administration of an ActRII antibody loading dose.

[0151] The method of embodiment II-1 or II-3, wherein the ActRII antibody loading dose is about 3 mg / kg to about 50 mg / kg.

[0152] The method of embodiment II-1 or II-3, wherein the ActRII antibody loading dose is about 10 mg / kg.

[0153] The method of embodiment II-1 or II-3, wherein the ActRII antibody loading dose is about 30 mg / kg.

[0154] The method of embodiment II-1 or II-3, wherein the ActRII antibody loading dose is a fixed dose of about 300 mg.

[0155] Embodiment II-8. A method according to any one of embodiments II-1 to II-7, wherein the ActRII antibody dosing regimen is initiated about 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, or about 5 weeks after the loading dose of the ActRII antibody.

[0156] Embodiment II-9. A method according to any one of embodiments II-1 to II-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg.

[0157] Embodiment II-10. The method of any one of embodiments II-1 to II-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 10 mg / kg.

[0158] Embodiment II-11. The method of any one of embodiments II-1 to II-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 30 mg / kg.

[0159] Embodiment II-12. A method according to any one of embodiments II-1 to II-11, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody approximately every 4 weeks, approximately every 8 weeks, approximately every 12 weeks, or approximately every 16 weeks.

[0160] The method of embodiment II-12, wherein the ActRII antibody dosing regimen comprises administration of the ActRII antibody about every 12 weeks.

[0161] The method of any one of embodiments II-1, II-3 to II-6, and II-8 to II-13, wherein the ActRII antibody loading dose is administered intravenously.

[0162] Embodiment II-15. The method of any one of embodiments II-1, and II-3 to II-13, wherein the ActRII antibody dosing regimen is administered intravenously.

[0163] Embodiment II-16. The method of any one of embodiments II-1, II-3 to II-6, and II-8 to II-13, wherein the ActRII antibody loading dose and the ActRII antibody dosing regimen are administered intravenously.

[0164] Embodiment II-17. A method according to any one of embodiments II-1 to II-7, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 200 mg to about 400 mg.

[0165] Embodiment II-18. The method of any one of embodiments II-1 to II-7, wherein the ActRII antibody dosing regimen comprises administration of the ActRII antibody at a dose of about 300 mg.

[0166] The method of embodiment II-17 or II-18, wherein the ActRII antibody drug regimen is administered once a week, twice a week, three times a week, or every two weeks.

[0167] The method of embodiment II-17 or II-18, wherein the ActRII antibody dosing regimen is administered once a week.

[0168] The method of embodiment II-7, wherein the ActRII antibody loading dose is administered subcutaneously.

[0169] The method of embodiment II-17 or II-18, wherein the ActRII antibody dosing regimen is administered subcutaneously.

[0170] The method of embodiment II-7, II-17, or II-18, wherein the ActRII antibody loading dose and the ActRII antibody dosing regimen are both administered subcutaneously.

[0171] Embodiment II-24. The method of embodiment II-1 or II-23, wherein the loading dose of ActRII antibody comprises an amino acid sequence of SEQ ID NO: 1 to 6.

[0172] Embodiment II-25. The method of any one of embodiments II-1 or II-3 to II-23, wherein the loading dose of the ActRII antibody comprises an amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto.

[0173] Embodiment II-26. A method according to any one of embodiments II-1 or II-3 to II-23, wherein the loading dose of ActRII antibody comprises an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0174] Embodiment II-27. The method of any one of embodiments II-1 or II-3 to II-13, wherein the loading dose of ActRII antibody is specific for ActRIIA and ActRIIB.

[0175] Embodiment II-28. A method according to any one of embodiments II-1 to II-27, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 1 to 6.

[0176] Embodiment II-29. A method described in any one of embodiments II-1 to II-27, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto.

[0177] Embodiment II-30. A method described in any one of embodiments II-1 to II-27, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0178] Embodiment II-31. A method according to any one of embodiments II-1 to II-27, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody specific for ActRIIA and ActRIIB.

[0179] Embodiment II-32. The method of any one of embodiments II-1 to II-31, wherein 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, and monogenic disorders associated with obesity.

[0180] The method of embodiment II-32, wherein the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

[0181] Embodiment II-34. The method of any one of embodiments II-1 to II-32, wherein the metabolic disorder is Prader-Willi syndrome.

[0182] The method of embodiment II-32, wherein the diabetes is type I diabetes or type II diabetes.

[0183] The method of embodiment II-32, wherein the method treats an obesity-related comorbidity selected from the group of impaired glucose tolerance, prediabetes, insulin resistance, high 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.

[0184] Embodiment II-37. The method of any one of embodiments II-1 to II-36, wherein the subject has a body mass index (BMI) of 30 or greater.

[0185] The method of any one of embodiments II-1 to II-36, wherein the subject has a BMI of 27 or greater and one or more obesity-related comorbidities.

[0186] Embodiment II-39. The method of any one of embodiments II-1 to II-38, wherein the subject is overweight.

[0187] Embodiment II-40. The method of any one of embodiments II-1 to II-39, wherein the subject is 18 years of age or older.

[0188] The method of any one of embodiments II-1 to II-39, wherein the subject is 45 years of age or older.

[0189] Embodiment II-42. The method of any one of embodiments II-1 to II-39, wherein the subject is a child aged 0 to 17 years.

[0190] Embodiment II-43. The method of any one of embodiments II-1 to II-42, wherein the treatment reduces body weight in the subject.

[0191] Embodiment II-44. The method of any one of embodiments II-1 to II-43, wherein the treatment reduces body fat mass in the subject.

[0192] Embodiment II-45. The method of any one of embodiments II-1 to II-44, wherein the treatment increases lean mass in the subject.

[0193] Embodiment II-46. The method of any one of embodiments II-1 to II-45, wherein the treatment reduces fat mass and increases lean mass in the subject.

[0194] Embodiment II-47. The method of any one of embodiments II-1 to II-44, wherein the treatment reduces body fat mass and preserves lean mass in the subject.

[0195] Embodiment II-48. The method of any one of embodiments II-1 to II-47, wherein the treatment reduces the subject's waist circumference.

[0196] Embodiment II-49. The method of any one of embodiments II-1 to II-47, wherein the treatment reduces liver and / or non-hepatic fat mass in the subject.

[0197] Embodiment II-50. The method of any one of embodiments II-1 to II-48, wherein the treatment improves glycemic control in the subject.

[0198] Embodiment II-51. The method of any one of embodiments II-1 to II-49, wherein the efficacy of the treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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 (36) Health Survey (SF-36) assessment, Homeostasis Model Assessment 2 (HOMA2), and physical activity monitoring via actigraphy.

[0199] Embodiment II-52. The efficacy of the treatment is determined by the desired "C trough The method of any one of embodiments II-1 to II-49, wherein the .alpha.-to- ...

[0200] Embodiment II-53. Desired "Ctrough The method of embodiment II-52, wherein " is 10 μg / ml.

[0201] Embodiment II-54. The method of any one of embodiments II-1 to II-53, wherein the subject is a human.

[0202] Embodiment Set III: Embodiment III-1. A method for treating a metabolic disorder in a subject in need of treatment, comprising administering to the subject an ActRII antibody dosing regimen, the ActRII antibody dosing regimen comprising administering an ActrII antibody at a dose of about 3 mg / kg to about 50 mg / kg once every about 8 weeks to about once every 16 weeks, wherein the ActRII antibody dosing regimen is administered intravenously.

[0203] The method of embodiment III-1, wherein the ActRII antibody dosing regimen follows administration of an ActRII antibody loading dose.

[0204] Embodiment III-3. A method according to any one of embodiments III-1 to III-2, wherein the ActRII antibody dosing regimen and / or loading dose of ActRII antibody comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 1 to 6.

[0205] Embodiment III-4. A method according to any one of embodiments III-1 to III-2, wherein the ActRII antibody dosing regimen and / or loading dose of ActRII antibody comprises administration of an ActRII antibody comprising the amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and the amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto.

[0206] Embodiment III-5. A method according to any one of embodiments III-1 to III-2, wherein the ActRII antibody dosing regimen and / or loading dose of ActRII antibody comprises administration of an ActRII antibody comprising the amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and the amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0207] Embodiment III-6. A method according to any one of embodiments III-1 to III-2, wherein the ActRII antibody dosing regimen and / or ActRII antibody loading dose comprises administration of an ActRII antibody specific for ActRIIA and ActRIIB.

[0208] Embodiment III-7. The method according to any one of embodiments III-1 to III-6, wherein 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, and monogenic disorders associated with obesity.

[0209] The method of embodiment III-7, wherein the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

[0210] Embodiment III-9. The method of any one of embodiments III-1 to III-6, wherein the metabolic disorder is Prader-Willi syndrome.

[0211] The method of embodiment III-7, wherein the diabetes is type I diabetes or type II diabetes.

[0212] Embodiment III-11. The method according to any one of embodiments III-7 to III-9, wherein the method treats an obesity-related comorbidity selected from the group consisting of impaired glucose tolerance, prediabetes, insulin resistance, high triglycerides, physical disorders associated with overweight, osteoporosis, renal disease, cardiometabolic disease, non-alcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

[0213] Embodiment III-12. The method of any one of embodiments III-1 to III-11, wherein the treatment reduces body weight in the subject.

[0214] Embodiment III-13. The method of any one of embodiments III-1 to III-12, wherein the treatment reduces body fat mass in the subject.

[0215] Embodiment III-14. The method of any one of embodiments III-1 to III-13, wherein the treatment increases lean mass in the subject.

[0216] Embodiment III-15. The method according to any one of embodiments III-1 to III-14, wherein the treatment reduces fat mass and increases lean mass in the subject.

[0217] Embodiment III-16. The method according to any one of embodiments III-1 to III-14, wherein the treatment reduces fat mass and preserves lean mass in the subject.

[0218] Embodiment III-17. The method according to any one of embodiments III-1 to III-16, wherein the treatment reduces the subject's waist circumference.

[0219] Embodiment III-18. The method of any one of embodiments III-1 to III-17, wherein the treatment reduces liver and / or non-hepatic fat mass in the subject.

[0220] Embodiment III-19. The method of any one of embodiments III-1 to III-18, wherein the treatment improves glycemic control in the subject.

[0221] Embodiment III-20. The method of any one of embodiments III-1 to III-19, wherein the efficacy of the treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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.

[0222] Embodiment III-21. The efficacy of the treatment is measured by measuring the C in a sample from the subject. trough The method according to any one of embodiments III-1 to III-20, wherein the measurement is performed by:

[0223] Embodiment III-22. Treatment comprises administering to a subject a sample of C trough But the desired "C trough " The method of embodiment III-21, wherein the method is effective when the .alpha.-amino acid concentration is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the .alpha.-amino acid concentration.

[0224] Embodiment III-23. Desired "C trough The method of embodiment III-22, wherein " is 10 μg / ml.

[0225] Embodiment III-24. The method of any one of embodiments III-1 to III-23, wherein the subject is a human.

[0226] Embodiment III-25. A method of treating a metabolic disorder in a subject in need of such treatment, comprising administering to the subject an ActRII antibody loading dose followed by an ActRII antibody dosing regimen.

[0227] The method of embodiment III-25, wherein the ActRII antibody loading dose is from about 3 mg / kg to about 50 mg / kg.

[0228] Embodiment III-27. The method of embodiment III-25 or III-26, wherein the ActRII antibody dosing regimen is initiated about 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, or about 5 weeks after the loading dose of the ActRII antibody.

[0229] Embodiment III-28. The method of any one of embodiments III-25 to III-27, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg.

[0230] Embodiment III-29. The method of any one of embodiments III-25 to III-28, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody about every 4 weeks, about every 8 weeks, about every 12 weeks, or about every 16 weeks.

[0231] The method of any one of embodiments III-25 to III-29, wherein the ActRII antibody loading dose is administered intravenously.

[0232] Embodiment III-31. The method of any one of embodiments III-25 to III-30, wherein the loading dose of the ActRII antibody and / or the ActRII antibody of the dosing regimen comprises an amino acid sequence of SEQ ID NO: 1 to 6.

[0233] Embodiment III-32. The method of any one of embodiments III-25 to III-30, wherein the ActRII antibody of the loading dose and / or the ActRII antibody of the dosing regimen comprises an amino acid sequence of SEQ ID NO: 7, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 8, or a sequence having at least 90% sequence identity thereto.

[0234] Embodiment III-33. A method according to any one of embodiments III-25 to III-30, wherein the ActRII antibody of the loading dose and / or dosing regimen of the ActRII antibody comprises an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

[0235] Embodiment III-34. The method of any one of embodiments III-25 to III-33, wherein the loading dose of ActRII antibody and / or the ActRII antibody dosing regimen is specific for ActRIIA and ActRIIB.

[0236] Embodiment III-35. The method of any one of embodiments III-25 to III-34, wherein 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, and monogenic disorders associated with obesity.

[0237] The method of embodiment III-35, wherein the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

[0238] Embodiment III-37. The method of any one of embodiments III-25 to III-34, wherein the metabolic disorder is Prader-Willi syndrome.

[0239] Embodiment III-38. The method of embodiment III-35, wherein the diabetes is type I diabetes or type II diabetes.

[0240] Embodiment III-39. The method of embodiment III-35, wherein the method treats an obesity-related comorbidity selected from the group of impaired glucose tolerance, prediabetes, insulin resistance, high triglycerides, physical disorders associated with overweight, osteoporosis, kidney disease, cardiometabolic disease, nonalcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

[0241] Embodiment III-40. The method of any one of embodiments III-25 to III-39, wherein the treatment reduces body weight in the subject.

[0242] The method of any one of embodiments III-25 to III-40, wherein the treatment reduces body fat mass in the subject.

[0243] Embodiment III-42. The method of any one of embodiments III-25 to III-41, wherein the treatment increases lean mass in the subject.

[0244] The method according to any one of embodiments III-25 to III-42, wherein the treatment reduces fat mass and increases lean mass in the subject.

[0245] The method according to any one of embodiments III-25 to III-43, wherein the treatment reduces fat mass and preserves lean mass in the subject.

[0246] Embodiment III-45. The method of any one of embodiments III-25 to III-44, wherein the treatment reduces the subject's waist circumference.

[0247] The method of any one of embodiments III-25 to III-45, wherein the treatment reduces liver and / or non-hepatic fat mass in the subject.

[0248] Embodiment III-47. The method of any one of embodiments III-25 to III-46, wherein the treatment improves glycemic control in the subject.

[0249] Embodiment III-48. The method of any one of embodiments III-25 to III-47, wherein the efficacy of the treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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.

[0250] Embodiment III-49. The efficacy of the treatment is measured by measuring the C in a sample from the subject. trough The method according to any one of embodiments III-25 to III-48, wherein the measurement is performed by

[0251] Embodiment III-50. Treatment comprises administering to a subject a sample of C trough But the desired "C trough " The method of embodiment III-49, wherein the method is effective when the .alpha.-methyl-2-pyridine derivative is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the .alpha.-methyl-2-pyridine derivative.

[0252] Embodiment III-51. Desired "C trough The method of embodiment III-50, wherein " is 10 μg / ml.

[0253] Embodiment III-52. The method of any one of embodiments III-25 to III-51, wherein the subject is a human.

[0254] The following examples are included for illustrative purposes and are not intended to limit the scope of the invention. EXAMPLES

[0255] Example 1: Design of a bimagrumab dosing model based on observed clinical population pharmacokinetics (PK) and pharmacodynamics (PD) A pharmacokinetic and pharmacodynamic (PK / PD) model was developed to support dose and frequency selection of an ActRII antibody (bimagrumab) for clinical studies to reduce fat mass (FBM) and increase lean body mass (LBM) in obese subjects. Bimagrumab has previously been tested in seven different Phase I, II, and III clinical trials to address different diseases with completely different dosing regimens (see Table 1).

[0256] To perform the pharmacokinetic and pharmacodynamic (PK / PD) analyses and modeling described herein, clinical studies were selected that provide PK and PD information in the following contexts: a wide dose range of bimagrumab intravenously (IV administration) from 10 to 3000 mg, various bimagrumab dosing timings, measurements of fat mass (FBM) and lean body mass (LBM) in response to bimagrumab, extensive study follow-up periods, and other diseases both obesity-related and non-related.

[0257] The pharmacokinetics (PK) of bimagrumab, as statistically evaluated and then modeled herein, include patient exposure (i.e., volume of distribution and clearance). The pharmacodynamics (PD) of bimagrumab, as statistically evaluated and then modeled herein, include effects on fat mass (FBM) and lean mass (LBM).

[0258] To determine safe and efficient dosing of bimagrumab, total fat mass (FBM) was selected as the primary pharmacodynamic (PD) endpoint and lean body mass (LBM) as the secondary endpoint. Research objectives include: 1. Statistically describe the PK characteristics of the bimagrumab clinical trial population 2. Statistically explain the PD effect on FBM and LBM in the bimagrumab clinical trial population 3. Statistically evaluate the relationship of subject-specific factors (i.e., age, weight, dose, and disease state) to bimagrumab PK (i.e., volume of distribution and clearance) and PD (i.e., FBM and LBM). 4. Perform PK / PD simulations to predict the exposure (PK) and effect (PD) of FBM and LBM for the following bimagrumab dosing regimens: a. 30 mg / kg bimagrumab administered intravenously (IV) every 4 weeks, 8 weeks, 12 weeks, and 24 weeks. b. 50 mg / kg of bimagrumab administered intravenously (IV) every 12 weeks 5. Perform PK / PD simulations to predict bimagrumab exposure (PK) and FBM and LBM effects (PD) for two loading doses 6. Run PK / PD simulations to predict exposure (PK) and FBM and LBM effects (PD) for a bimagrumab dosing regimen using a loading dose at week 0 and every 12 weeks thereafter, as follows: a. 10 mg / kg IV at weeks 0, 4, and 16 b. 30 mg / kg IV at weeks 0, 4, and 16 7. Investigate the effect of body weight on bimagrumab exposure (PK) and FBM and LBM effects (PD) [Table 3]

[0259] Example 2: Modeling Method software For PK parameter estimation and diagnostic plots, the validated version Monolix Suite 2019R2 was used (Monolix version 2019R2. Antony, France: Lixoft SAS, 2019.). For human PK / PD simulations, Simulx (Monolix Suite 2019R2), validated versions of lixoftConnectors 2019.2, mlxR 4.2.0 (Lavielle M. mlxR: Simulation of longitudinal data. Version 4.0.0.2019. www.simulx.webpopix.org.) and R 4.1.1 (R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, 2008, www.Rproject.org.) were used.

[0260] Guidelines Data analysis followed the FDA Guidance for Industry on Population Pharmacokinetics (FDA 1999), the EMA guideline on PopPK analyses (EMA 2007), and the LYO-X standard operating procedures (SOP) from the QMS Version 3.74.

[0261] Data programming and QC Individual PK, dual energy x-ray absorptiometry (DXA), demographic data, and dosing information were used. Data from all studies were merged into a single PK / PD analysis dataset. Automated quality control (QC) checks of the analysis dataset were performed using scripts to ensure the formal accuracy of the dataset for population PK / PD modeling with Monolix. QC output indicated that there were no errors in the dataset programming. The analysis dataset included 743 subjects. The total number of observations was 10,006, of which 688 (6.9%) were below the limit of quantification.

[0262] Handling missing data and outliers No outliers were identified via visual inspection of the data and no further steps were taken to identify and handle outliers. There were no missing values ​​in the analysis dataset. Data below the limit of quantitation (BLQ) were included in the population PK analysis using the censoring methods available in Monolix.

[0263] Parameter Estimation Population parameters were estimated using the SAEM algorithm implemented in Monolix. The number of iteration steps k1 and k2 were set to 700 and 200. SAEM convergence plots confirmed that the number of iteration steps was large enough to converge to stable parameter estimates in all cases. Initial estimates of fixed effect parameters were determined by manually fitting the model to the data using the "Check initial fixed effects" function in Monolix. The initial standard deviation of the random effects was set to 1. For successive modeling steps, parameter estimates from the previous model were used as initial estimates for the next modeling step. Standard errors of parameter estimates were derived from the Fisher information matrix using stochastic approximation. Conditional means and standard deviations were calculated for individual parameters. For the stopping rule of individual parameter estimates, the MCMC evaluation length (L_mcmc) was set to 50. The -2 log likelihood (-2LL) was calculated using importance sampling with a Monte Carlo chain length of 15,000. We verified that this Monte Carlo chain is sufficiently long via the standard error of the -2LL estimate.

[0264] Model Development Approach For development of basic model diagnostic plots, standard errors of parameter estimates and -2LL were used as selection criteria.

[0265] For covariate model building, correlation plots of individual parameter estimates versus covariates were used to select covariates for testing. Covariates with p-values ​​>0.01 were retained in the model.

[0266] Diagnostic plots All diagnostic plots were constructed using Monolix. Visual predictive checks (VPCs) were based on 500 simulations using the design structure (i.e., dosing, timing, covariates, and sample size) of the model and the observed data. VPCs compared the median and 10th and 90th percentiles of the simulated data with the corresponding percentiles of the observed data. For some VPC plots, 90 percent (%) prediction intervals for the simulated percentiles were also shown. Binning was manually adjusted to obtain well-spaced bins with a sufficient number of observations within each bin. For details on constructing VPCs, see Chapter 9.7 of Lavielle 2014 (M. Lavielle. Mixed Effects Models for the Population Approach: Models, Tasks, Methods and Tools. Chapman and Hall / CRC, 2014).

[0267] Observed versus predicted plots, standardized random-effects boxplots, histograms of individual parameters, and covariate versus parameter and residual plots were constructed using random sampling from the conditional distributions of the individual parameters (Lavielle and Ribba 2016). BLQ data were included in the diagnostic plots by sampling the BLQ data from the conditional distributions (A. Samson, M. Lavielle, F. Mentre. Extension of the SAEM algorithm to left-censored data in nonlinear mixed-effects model: Application to HIV dynamics model. Computational Statistics & Data Analysis. 2006, 51(3):1562-74).

[0268] For the residual plots, we used the individual weighted residuals (IWRES), population weighted residuals (PWRES) and normalized prediction distribution errors (NPDE). IWRES is an estimate of the standardized residuals based on individual predictions, PWRES is the normalized difference between the observations and their mean, and NPDE is a non-parametric version of PWRES based on rank statistics (E. Comets, K. Brendel, and F. Mentre. Computing normalized prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Computer Methods and Programs in Biomedicine. 2008, 90(2):154-166). The residual plots further show the 10%, 50% and 90% quantiles. Details on the definition and calculation of the residuals are provided in (Lavielle 2014).

[0269] Simulation Methodology PK / PD simulations were performed in R using the Simulx mlxR library. In mlxR, simulation model files were automatically generated using Monolix results as input to the function monolix2simulx( ). Simulations were performed with and without inter-patient variability. Observed values ​​were set to zero. Covariate effects were included in the simulations. For each simulation scenario (dose and patient group), 2500 individuals were simulated and summary statistics were calculated. For calculation of area under the curve (AUC), the trapezoidal rule was used for the simulated PK parameters.

[0270] Structural Model The model describing the PK of bimagrumab in humans was two-compartmental with first-order clearance from a central compartment and Michaelis-Menten clearance. This was in accordance with the known PK properties of monoclonal antibodies that bind to cell surface targets that undergo target-mediated pharmacokinetics (TMDD). The equation was:

number

[0271] FBM is the production rate k FBM-in and first-order elimination rate k FBM-out The LBM was described using a turnover model with a production rate of k LBM-out and first-order elimination rate k LBM-out It has been described using a turnover model having the following structure:

number

[0272] The effect of bimagrumab on FBM was evaluated by comparing serum bimagrumab concentrations with the production rate (E FBM-in ) or disappearance rate (E FBM-out The effect on LBM was modeled by coupling the serum bimagrumab concentration to the production rate (E LBM-in The effects of the out rate on the pulmonary circulation were modelled by combining the effects on the out rate with the effects on the pulmonary circulation. Three different effect models were tested. A linear model of the effect on the out rate was written as follows: E out =1+slope Cc

[0273] The exponential model of the effect on exit velocity is written as follows: E out =1-I max (e -k Cc -1), and the effects on in rate are noted below. E in =1+I max (1-e -k Cc )

[0274] The Emax model for the effect on exit velocity is written as follows:

number

number

[0275] A schematic diagram of the PK / PD model is shown in Figure 6.

[0276] Statistical model Each parameter was modeled as a random variable with a log-normal distribution. The equation for each parameter was: φ i =φ pop e η In the formula, φ pop were typical parameters of the population, and η was a random variable with mean 0 and standard deviation ω. A combined error model was used to model the observed values ​​of bimagrumab, FBM, and LBM: y obs =y pred +(a+b y pred )·ε In the formula, y obs is the observation, and y pred is the model prediction, ε is an independent random variable normally distributed with mean 0 and variance 1. Parameter a describes the standard deviation of the systematic error and parameter b describes the proportionality coefficient. Continuous covariates were modeled with the following equation:

number

[0277] PK / PD model development Model development was performed in three steps. In the first step, a basic PK model was developed, followed by a PK covariate model. In the second step, the FBM PD model was developed, and in the third step, the LBM PD model was added. Thus, the final model related the dose and PK, as well as the effect of bimagrumab on FBM and LBM.

[0278] A. Development of PK model Based on the known PK properties of the immunoglobulin IgG1 molecule and that binding to cell surface receptors may result in target-mediated pharmacokinetics (TMDD) as evident from the PK clinical trial profile, a two-compartment PK model with linear and Michaelis-Menten clearance was tested. This model described the data as judged by the diagnostic plots and no further refinement of the basic model was required. Correlation plots between body weight, clearance, and central volume of distribution showed correlation values ​​of >0.3. These covariate relationships were tested and found to be statistically significant (p<10 -15 ). The -2 log likelihood (-2LL) for the model with the covariates was large but was selected for the highly significant covariate coefficients. Correlation plots showed no effects between study, age, and sex and any of the PK parameters; therefore, their effects were included in the final covariate model.

[0279] B. Development of FBM model A turnover model of FBM was used with FBM at baseline as a regressor. Baseline FBM was used as a regressor because there was a large interpatient variability in baseline values, which would have yielded population predictions far from individual predictions. The effect of bimagrumab was on either FBM input or disappearance rates. Sigmoid and exponential effect models were tested. Models with an effect on output rate were better with -2LL. Closer inspection of the data showed that in some patients, FBM increased over the course of treatment. For this reason, normal distribution parameters were tested to describe the maximum effect (max_effect), which allows negative values ​​to explain the increase in FBM. A model with an exponential effect on output FBM rate was selected based on the lowest -2LL and its ability to explain increasing FBM.

[0280] C. Development of LBM model A turnover model of FBM was used to apply the effect of bimagrumab to the LBM input rate. Because bimagrumab's mechanism of action suggests the regulation of muscle growth, not muscle loss, the effect on the rate of LBM loss was not tested. For the same reasons as the FBM model, LBM at baseline was used as a regressor variable. The effect model tested was an exponential model. This model provided good model fit, as judged by diagnostic plots. To capture possible relationships between FBM and LBM, correlations between potency on FBM and LBM, and correlations between FBM and LBM loss rates were included in the model to capture correlations between maximum effects on FBM and LBM. Although this model was worse by -2LL, it was decided to retain these correlations to ensure that only realistic combinations of maximum effects, turnover rates, and potencies of FBM and LBM were used in the simulations.

[0281] Example 3: Patient demographics observed from seven clinical trials of bimagrumab As described in Example 1, seven clinical trials of bimagrumab with completely different dosing regimens were statistically analyzed for PK and PD characteristics. It was observed that individual lean body mass (LBM) increased along with fat body mass (FBM) at baseline (Figure 1). Lean body mass, and possibly also fat body mass, at baseline decreased with age (Figures 2 and 3). Thus, body weight appeared to decrease with age (Figure 4). The age range across all included studies was 26-96 years, body weight range was 35-110 kg, lean body mass range was 20.3-80 kg, and fat body mass range was 1.5-48.3 kg. 42% of all subjects were male. Tables 2 and 3 below show summary statistics for age, body weight, lean body mass, fat body mass, BMI, and sex by study, as well as the total PK / PD analysis dataset. [Table 4] [Table 5]

[0282] Figure 5 shows the relationship between percent change in LBM and FBM relative to baseline. Changes in LBM ranged from approximately 90-120%, while changes in FBM ranged from approximately 70-120%. For treated patients, a reduction in FBM from 100-95% was associated with an increase in LBM of 100-105% on average, as can be seen from the spline fits. A further reduction in FBM from 95% to 70% was not associated with any further change in LBM, which remained at 105% on average. As is evident from the spline fits, there was on average a much stronger placebo response in the relative change in FBM and almost none in LBM.

[0283] Bimagrumab had typical IgG1 characteristics with a central volume of distribution of 3.16 L, a peripheral volume of distribution of 5.33 L, and a terminal half-life of 22.46 days. Binding to ActRII was characterized by a Km of 0.0414 mg / mL and a V of 0.607 mg / L / day. maxThis resulted in target-mediated pharmacokinetics (TMDD) with

[0284] Fat mass (FBM) had a natural elimination half-life of 322 days compared with 25 days for lean body mass (LBM). Therefore, the onset of effect and return to baseline after treatment was predicted to be much more rapid for LBM than for FBM. EC 50 The EC values ​​for LBM and FBM were 0.76 mg / mL and 0.38 mg / mL, respectively. Thus, bimagrumab acted on FBM and LBM in a similar concentration range. The individual EC values ​​for LBM and FBM were 50 The correlation between was strong (R = 0.919), whereas the correlation between the maximum individual effects on LBM and FBM was weak (R = 0.239). There was no correlation between LBM and FBM turnover rates. Thus, although LBM and FBM turnover may differ for individual subjects, the effect of bimagrumab is expected to be strongly dependent on fat mass and muscle mass. There was no effect of age, sex, or weight on any of the FBM and LBM PD parameters. Furthermore, the response was the same for otherwise healthy subjects with hip fracture, patients with COPD, subjects with sarcopenia, or subjects with metabolic disorders.

[0285] Body weight was found to be a statistically significant covariate for clearance (b=0.619) and central volume of distribution (b=0.661). This effect of body weight is roughly consistent with that expected for an IgG1 molecule. Gender and age did not show any effect on exposure. Inter-patient variability was expected and low for parameters related to PK and non-specific clearance after IV administration.

[0286] Example 4: PK and PD statistics of observed clinical trials versus dosing regimen model predictions Dosing regimen models were evaluated and determined to accurately describe the observed clinical data without bias or other deviations.

[0287] PK model evaluation Goodness-of-fit (GoF) plots were generally good with no bias, except for the clinical concentrations of bimagrumab, which were less than 1ug / mL (Figures 7 and 8). Visual predictive checks (VPCs) across all clinical trial data (Figure 9), as well as VPCs by weight group of the clinical population, showed that the model accurately described the median and the 10th and 90th percentiles (Figure 10). Histograms of simulated individual clinical trial patient parameters showed that the estimated parameters were consistent with the statistical model, with the exception of Km, which appeared to have some values ​​much larger than the typical population values. There were no trends between the individual random effects and the gender, weight, or age of the clinical trial patients, indicating that an appropriate covariate model was used.

[0288] FBM and LBM model evaluation The FBM goodness of fit (GoF) plots and VPC plots (Figures 11 and 12) had no bias between the observed clinical patient population and individual FBM values ​​and the model predicted FBM values. The LBM goodness of fit (GoF) plots and VPC plots (Figures 13 and 14) were also unbiased, indicating that the model described LBM without bias.

[0289] The simulated individual parameters also demonstrated that the estimated parameters of the predictive PK / PD model were consistent with the statistically derived parameters.

[0290] In summary, model evaluation showed that the final model described the observed data well without any bias or other deviations. Therefore, the population PK / PD model was deemed appropriate to predict bimagrumab exposure and effects on FBM and LBM for different dosing regimen scenarios.

[0291] Example 5: Model prediction of bimagrumab dosing regimens on exposure (PK) and FBM and LBM (PD) The predicted effective fat mass half-life was simulated versus bimagrumab concentration. The apparent saturation concentration of the ActRII receptor based on this curve is approximately 10 μg / ml. Therefore, it is advantageous to maintain serum concentrations of bimagrumab above 10 μg / ml.

[0292] PK / PD simulations were performed to predict the exposure and effect of bimagrumab 30 mg / kg administered by IV every 4, 8, 12, or 24 weeks. 50 mg / kg administered every 12 weeks was also tested. Treatment was modeled for 24 months. Figure 15 shows the median exposure of the IV dosing regimens and Figure 16 shows the effect on LBM and FBM as percent (%) change from baseline. Figure 17 shows the effect of bimagrumab dosage on FBM+LBM. Table 4 shows summary statistics of predicted effect of bimagrumab dosage FBM and LBM effect at 6, 12, 18, and 24 months. [Table 6]

[0293] Loading dose effect PK / PD simulations were then performed to predict the exposure and efficacy of bimagrumab at 10 mg / kg or 30 mg / kg administered IV every 12 weeks, with and without a loading dose of the same concentration, respectively. Figure 18 shows the median exposure for the dosing regimens with and without a loading dose. Notably, the addition of a loading dose to the 30 mg / kg dosing regimen increased the C trough (as shown in FIG. 18), which is predicted to be a saturating concentration of the ActRII receptor (FIG. 24). Thus, a dosing regimen of 30 mg / kg every 12 weeks with at least one loading dose is predicted to allow for continuous fat loss.

[0294] Figure 19 shows the predicted effect on LBM and FBM as percent (%) change from baseline. Figure 20 shows the predicted effect of bimagrumab dose on FBM+LBM. Table 5 and Figure 21 show summary statistics for the predicted effect of bimagrumab dosage on FBM and LBM effects at 24, 36, and 48 weeks. [Table 7]

[0295] Predictive effect of body weight on PK and PD of bimagrumab PK / PD simulations were performed to evaluate the effect of body weight on the PK and PD effects of bimagrumab administration. Subjects with population-typical parameters and body weights between 60 and 140 kg were simulated. Figures 22 and 23 show the bimagrumab concentration versus time profile (PK) and effect on FBM (PD), respectively. The bimagrumab peak serum concentration (Cmax) and 24-week area under the curve (AUC) were calculated from bimagrumab exposure per body weight and are summarized in Tables 6 and 7. [Table 8] [Table 9]

[0296] The median predicted effects on FBM at week 48 for the low-dose bimagrumab regimen with a loading dose (10 mg / kg administered IV at weeks 0, 4, 16, 28, and 40) and the high-dose regimen with a loading dose (30 mg / kg administered IV at weeks 0, 4, 16, 28, and 40) were 84 and 79.8 for baseline FBM and 104.6 and 105.9 for baseline LBM.

[0297] PK / PD simulations showed that the effect on LBM was much faster, with steady state achieved within 3 months, whereas the time to steady state for FBM took at least 2 years. In particular, due to the different effect kinetics in FBM and LBM, it was predicted that patients would first gain weight for about 2-3 months after starting treatment with bimagrumab, and then begin to lose weight compared to baseline due to the larger effect size on FBM. After treatment cessation, the effect on LBM was lost within about 3 months, whereas the effect on FBM took about 1 year to return to half of the effect size.

[0298] In particular, the addition of a loading dose to the 30 mg / kg dosing regimen increased C trough (as shown in FIG. 18), which is predicted to be a saturating concentration of the ActRII receptor (FIG. 24). Thus, a dosing regimen of 30 mg / kg every 12 weeks with at least one loading dose is predicted to allow for continuous fat loss.

[0299] Example 6: Evaluation of bimagrumab dosing in overweight or obese adults The randomized, placebo-controlled trial was designed to evaluate dosing of bimagrumab in overweight or obese adults aged 45 years or older. The objective of the study was to evaluate the effect of bimagrumab on fat loss in adults aged 45 years or older who are obese or overweight with at least one obesity-related comorbidity.

[0300] The bimagrumab dosing regimens compared herein include a high dose regimen (30 mg / kg) and a low dose regimen (10 mg / kg) administered every 12 weeks. Both bimagrumab dosing regimens are preceded by a loading dose (week 0) 4 weeks prior to the start of the dosing regimen.

[0301] Main purpose To determine a safe and effective dose of bimagrumab for central obesity and fat mass reduction, as measured by change in waist circumference (cm) from baseline from Week 0 to Week 24.

[0302] Secondary Objectives I. To evaluate the safety and tolerability of bimagrumab dosages. II. To evaluate the effect of bimagrumab on change in lean mass (kg and % change) from baseline from weeks 0 to 24 as measured by DXA. III. To evaluate whether bimagrumab improves muscle strength as measured by manual dynamometry from baseline to weeks 0 to 24. IV. To evaluate the effect of bimagrumab on change in body fat mass (kg and % change) from baseline from weeks 0 to 24 as measured by DXA. V. To assess change from baseline in body 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. 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 the 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). XII.To evaluate the effect of bimagrumab using change in bioimpedance (percent change in ohms) from baseline from week 0 to week 24. XIII. To determine changes in all primary and secondary objectives from Week 24 to Week 36.

[0303] Efficacy endpoints To determine the efficacy of bimagrumab on fat mass reduction, the following markers will be evaluated: waist circumference, blood pressure, fat mass by dual-energy x-ray absorptiometry (DXA), lean mass by DXA, body weight, body mass index (BMI), lipid levels (total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG)), HgbA1c levels, glucose levels, insulin levels, Short Form Physical Performance Battery (SPPB), physical activity monitoring via actigraphy, Impact of Weight on Quality of Life (IWQoL-Lite for CT) assessment, Short Form (36) Health Survey (SF-36), exploratory urinary biomarkers (e.g., microalbumin); leptin, adiponectin, adipsin, IL-18, and IL-6 as adipose tissue biomarkers, and activin A as a pharmacodynamic (PD) biomarker.

[0304] 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).

[0305] Study design This study is a randomized, partially blinded, placebo-controlled, three-arm study. Participants will be randomized to one of the following treatment arms, including a loading dose: a) Bimagrumab placebo b) Bimagrumab 10mg / kg c) Bimagrumab 30mg / kg

[0306] Bimagrumab and bimagrumab placebo treatment will be blinded. The study will consist of a screening visit to assess eligibility, followed by clinic visits and phone contacts every 4 weeks during treatment until follow-up at week 24. An end-of-study visit will occur at week 36.

[0307] Dosage and mode of administration of investigational drug As described above in the study design, bimagrumab will be administered by intravenous (IV) infusion at doses of 10 mg / kg or 30 mg / kg at weeks 0 (loading dose), 4, and 16. This dosing regimen will be every 12 weeks, with an additional loading dose at week 0 prior to the start of the week 4 dosing regimen.

[0308] The rationale for the 24-week exposure period and assessment of the primary endpoint is that this period allows time to observe any differences in effect from the bimagrumab dose compared to placebo.

[0309] Reference Therapeutic Dosage and Mode of Administration Bimagrumab placebo will be administered by IV infusion in 5% dextrose in water (D5W) for two doses, one at week 0 and a second at week 12.

[0310] 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.

[0311] An alternative study paradigm includes a 48-week treatment period with bimagrumab administered by intravenous (IV) infusion at weeks 0 (loading dose), 4, 16, 28, and 40 at either 10 mg / kg or 30 mg / kg each.

[0312] Selection Criteria 1. Written informed consent must be obtained prior to any study-related evaluations. 2. Men and women aged ≥ 45 years. 3. BMI ≥ 30 or BMI ≥ 27 with one or more obesity-related comorbidities. 4. Have a stable weight (± 3 kg) within 3 months of screening. 5. Self-reported failure of at least one dietary effort to lose weight 6. Able to communicate satisfactorily with the investigator, comply with study requirements, and adhere to diet and activity programs for the duration of the study.

[0313] 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 for a longer period if required by other restrictions on clinical trial participation based on local regulations. 3. Patient weight >150kg 4. History of clinically significant conditions, e.g., cardiovascular disease, pulmonary disease, or osteoarthritis, that prevent regular walking for exercise. 5. Deficit of 500 calories per day, contraindication to high protein diet. 6. Pregnant or breastfeeding women. 7. Females of childbearing potential, defined as any female of physiological reproductive potential, who must use highly effective contraception during treatment with bimagrumab and for 6 months after the final dose. Highly effective contraceptive methods include: 1. Total abstinence. Periodic abstinence (e.g., calendar, ovulation, symptomatic, postovulatory methods) and pull-out methods are not acceptable methods of contraception. 2. 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. 3. 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. 4. 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 devices or systems. c) Barrier contraceptive methods, such as condoms or occlusive caps (diaphragm or cervical / fornix caps) with spermicidal foams / gels / films / creams / vaginal suppositories.

[0314] If using oral contraceptives, women must have been taking the same pill steadily for at least 3 months prior to receiving study treatment.

[0315] Women are considered to be postmenopausal and not of childbearing potential if they have had natural (spontaneous) 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 6 weeks previously. In the case of oophorectomy alone, women are considered to be of no childbearing potential only if follow-up hormone level evaluation has confirmed their reproductive status. 8. History of treated or untreated malignancy of any organ system within the past 5 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. 9. Personal or family history of medullary thyroid cancer or a personal or family history of multiple endocrine neoplasia syndrome type 2 10. Diseases other than cancer known to cause cachexia or muscle wasting, or GI malabsorption disorders associated with lipodystrophy. 11. Diagnosis of diabetes mellitus and current use of any antidiabetic medication. Does not exclude metabolic syndrome, even if controlled with antidiabetic medications such as metformin or SGLT2 inhibitors. 12. 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. 13. Significant psychiatric disorder, clinically significant 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). 14. Known heart failure classified as New York Heart Association Class III and IV or history of chronic hypotension (systolic blood pressure <100 mmHg). 15. Systolic blood pressure >180 or <90mmHg, or diastolic blood pressure >100 or <50mmHg at screening, or malignant hypertension. 16. ECG showing clinically significant abnormalities, including current supraventricular arrhythmias with uncontrolled ventricular response at rest (mean heart rate >100 beats per minute [bpm]) despite medical or device therapy, or a history of either spontaneous or induced sustained ventricular tachycardia (heart rate >100 bpm for 30 seconds) despite medical or device therapy, or a history of resuscitated cardiac arrest or the presence of an automated internal cardioverter-defibrillator. 17. 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. 18. Long QT syndrome or QTcF > 450 ms (Fridericia corrected) for men and QTcF > 470 ms for women at baseline at screening or repeat assessment. 19. Significant blood coagulation disorder, 75,000 / mm 3 platelet count less than 1.0 g / dL, and hemoglobin less than 11.0 g / dL. 20. Liver disease or injury (excluding Gilbert's disease) as indicated by abnormal liver function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum bilirubin. Investigators must adhere to the following criteria:

[0316] 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.

[0317] If the total bilirubin concentration increases above 1.5 × ULN, then the total bilirubin should be differentiated into direct and indirect reactant bilirubin. In either case, serum bilirubin should not exceed a value of 1.6 mg / dL (27 μmol / L). 21. History or presence of severe acute or chronic liver disease (compensated or decompensated), known gallbladder or bile duct disease, acute or chronic pancreatitis, acute renal failure or chronic renal failure stage 3 or greater. 22. History of Hepatitis B or HIV. Successfully treated history of Hepatitis A or C is not excluded. 23. 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. 24. Lack of peripheral venous access. 25. Donation or loss of ≥400 mL of blood within 8 weeks prior to administration of the loading dose, or longer if required by local regulations, or plasma donation (>250 mL) within 14 days prior to first dose. 26. Any acute illness affecting lower extremity function or the patient's ability to participate in the study, in the opinion of the investigator, within 30 days prior to the Screening visit. 27. Smoking more than one pack of cigarettes daily. 28. Cannabis use more than twice a week. 29. Consumption of five or more alcoholic drinks on the same occasion on each of five or more days in the past 30 days. 30. Family history of hypertriglyceridemia or personal history of fasting triglycerides greater than 500 mg / dl (5.65 mmol / L).

Claims

1. 1. A method of treating a metabolic disorder in a subject in need of such treatment, comprising administering to the subject an ActRII antibody dosing regimen, wherein the ActRII antibody dosing regimen comprises administering an ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg about once every 8 weeks to about once every 16 weeks, wherein the ActRII antibody dosing regimen is administered intravenously.

2. 2. The method of claim 1, wherein the ActRII antibody dosing regimen follows administration of an ActRII antibody loading dose.

3. The method of claim 2, wherein the ActRII antibody dosing regimen and / or the ActRII antibody loading dose comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO:1-6.

4. The method of claim 1, wherein the ActRII antibody dosing regimen and / or the ActRII antibody loading dose comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO:7, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO:8, or a sequence having at least 90% sequence identity thereto.

5. The method of claim 1, wherein the ActRII antibody dosing regimen and / or the ActRII antibody loading dose comprises administration of an ActRII antibody comprising an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

6. 2. The method of claim 1, wherein the ActRII antibody dosing regimen comprises administration of an ActRII antibody specific for ActRIIA and ActRIIB.

7. 2. The method of claim 1, wherein 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, and monogenic disorders associated with obesity.

8. 8. The method of claim 7, wherein the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity resulting from a mutation 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

9. 2. The method of claim 1, wherein the metabolic disorder is Prader-Willi syndrome.

10. 8. The method of claim 7, wherein the diabetes is type I diabetes or type II diabetes.

11. 8. The method of claim 7, wherein the method treats an obesity-related comorbidity selected from the group of impaired glucose tolerance, pre-diabetes, insulin resistance, high triglycerides, overweight-related physical disorders, osteoporosis, kidney disease, cardiometabolic disease, non-alcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

12. 10. The method of claim 1, wherein the treatment reduces body weight in the subject.

13. The method of claim 1 , wherein the treatment reduces body fat mass in the subject.

14. The method of claim 1 , wherein the treatment increases lean mass in the subject.

15. 10. The method of claim 1, wherein the treatment reduces fat mass and increases lean mass in the subject.

16. 10. The method of claim 1, wherein the treatment reduces fat mass and preserves lean mass in the subject.

17. The method of claim 1 , wherein the treatment reduces waist circumference in the subject.

18. 10. The method of claim 1, wherein the treatment reduces liver and / or non-hepatic fat mass in the subject.

19. The method of claim 1 , wherein the treatment improves glycemic control in the subject.

20. 10. The method of claim 1, wherein the effectiveness of said treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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 (36) Health Survey (SF-36) assessment, Homeostasis Model Assessment 2 (HOMA2), and physical activity monitoring via actigraphy.

21. The efficacy of the treatment is determined by measuring the C ｔｒｏｕｇｈ The method of claim 1, wherein the concentration is measured by

22. The treatment comprises: ｔｒｏｕｇｈ However, the desired "C ｔｒｏｕｇｈ 22. The method of claim 21, wherein the method is effective when the .alpha.-amino acid concentration is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the .alpha.-amino acid concentration.

23. The desired "C ｔｒｏｕｇｈ " is 10 μg / ml.

24. The method of claim 1 , wherein the subject is a human.

25. A method of treating a metabolic disorder in a subject in need of such treatment, comprising administering to the subject an ActRII antibody loading dose followed by an ActRII antibody dosing regimen.

26. 26. The method of claim 25, wherein the ActRII antibody loading dose is from about 3 mg / kg to about 50 mg / kg.

27. The method of claim 25, wherein the ActRII antibody dosing regimen is initiated about 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, or about 5 weeks after the loading dose of the ActRII antibody.

28. The method of claim 25, wherein the ActRII antibody dosing regimen comprises administration of the ActRII antibody at a dose of about 3 mg / kg to about 50 mg / kg.

29. 26. The method of claim 25, wherein the ActRII antibody dosing regimen comprises administration of the ActRII antibody about every 4 weeks, about every 8 weeks, about every 12 weeks, or about every 16 weeks.

30. 26. The method of claim 25, wherein the ActRII antibody loading dose is administered intravenously.

31. 26. The method of claim 25, wherein the ActRII antibody of the loading dose and / or the ActRII antibody of the dosing regimen comprises the amino acid sequence of SEQ ID NO:1-6.

32. 26. The method of claim 25, wherein the ActRII antibody of the loading dose and / or the ActRII antibody of the dosing regimen comprises an amino acid sequence of SEQ ID NO:7, or a sequence having at least 90% sequence identity thereto, and comprises an amino acid sequence of SEQ ID NO:8, or a sequence having at least 90% sequence identity thereto.

33. 26. The method of claim 25, wherein the ActRII of the loading dose and / or the ActRII antibody of the dosing regimen comprises an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 90% sequence identity thereto, and an amino acid sequence of SEQ ID NO: 10, or a sequence having at least 90% sequence identity thereto.

34. 26. The method of claim 25, wherein the ActRII antibody of the loading dose and / or the ActRII antibody of the dosing regimen is specific for ActRIIA and ActRIIB.

35. 26. The method of claim 25, wherein 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, and monogenic disorders associated with obesity.

36. 36. The method of claim 35, wherein the monogenic disorder associated with obesity is one of Bardet-Biedl syndrome or obesity resulting from a mutation 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, MKKS, MKS1, MRAP2, NTRK2, PCSK1, PHF6, POMC, SH2B1, SIM1, TMEM67, TRIM32, TTC8, and VPS13B.

37. 26. The method of claim 25, wherein the metabolic disorder is Prader-Willi syndrome.

38. 36. The method of claim 35, wherein the diabetes is type I diabetes or type II diabetes.

39. 36. The method of claim 35, wherein the method treats an obesity-related comorbidity selected from the group of impaired glucose tolerance, pre-diabetes, insulin resistance, high triglycerides, overweight-related physical disorders, osteoporosis, kidney disease, cardiometabolic disease, non-alcoholic fatty liver disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, and / or gallstones.

40. 26. The method of claim 25, wherein the treatment reduces body weight in the subject.

41. 26. The method of claim 25, wherein the treatment reduces body fat mass in the subject.

42. 26. The method of claim 25, wherein the treatment increases lean mass in the subject.

43. 26. The method of claim 25, wherein said treatment reduces fat mass and increases lean mass in said subject.

44. 26. The method of claim 25, wherein said treatment reduces body fat mass and preserves lean mass in said subject.

45. 26. The method of claim 25, wherein the treatment reduces waist circumference in the subject.

46. 26. The method of claim 25, wherein said treatment reduces liver and / or non-hepatic fat mass in said subject.

47. 26. The method of claim 25, wherein the treatment improves glycemic control in the subject.

48. 26. The method of claim 25, wherein the efficacy of the treatment is measured by at least one of the following: body weight, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), 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 (36) Health Survey (SF-36) assessment, Homeostasis Model Assessment 2 (HOMA2), and physical activity monitoring via actigraphy.

49. The efficacy of the treatment is determined by measuring the C ｔｒｏｕｇｈ The method of claim 25, wherein the concentration is measured by

50. The treatment comprises: ｔｒｏｕｇｈ However, the desired "C ｔｒｏｕｇｈ 50. The method of claim 49, wherein the method is effective when the .alpha.-amino acid concentration is at least about 500%, about 400%, about 300%, about 200%, about 100%, about 90%, about 80%, or about 75% of the .alpha.-amino acid concentration.

51. The desired "C ｔｒｏｕｇｈ " is 10 μg / ml.

52. 26. The method of claim 25, wherein the subject is a human.

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