Myostatin, activin, or activin receptor antagonist for use in the treatment of obesity and related conditions

Abstract

Methods for treating obesity and related comorbidities, such as type II diabetes, by decreasing body fat mass while increasing lean mass, and thereby decreasing central adiposity, are provided. The method includes administering myostatin or activin or an activin receptor antagonist, preferably an anti-ActRII receptor antibody such as bimagrumab.

Description

[Technical Field]

[0001] This invention improves body composition, that is, by reducing body fat mass while reducing lean body mass. By increasing and thereby reducing central fat accumulation, Myostatin for use in the treatment of diabetes and related comorbidities, e.g., type II diabetes. Cucivin or GDF11 antagonist or receptor antagonist, in the administration regimen To relate to. [Background technology]

[0002] In 2014, it was estimated that over 1.9 billion adults worldwide (39%) were overweight. Of those, 600 million (13%) were obese (World Health Organization) (Zation 2015). Recent estimates suggest that there are approximately 78 million new cases in the United States. The person is obese (Jensen et al 2014), and 69% are overweight or obese. It is one of the following, and it has been shown that 35% are obese (Ogden et al 2014). Obesity is a risk factor for overall mortality, accounting for 3.4 million deaths worldwide in 2010. It is presumed to have occurred (Lim et al 2012). Type 2 diabetes, hypertension, lipid Many comorbidities, such as abnormal heart conditions and coronary heart disease, are associated with obesity (Apovian (et al 2015). Insulin resistance is a state of resistance to insulin, This reduces the effectiveness of luminol, causing a decrease in glucose uptake in muscle tissue, and This impairs glucose oxidation and glycogen synthesis, as well as hepatic glucose in the liver. This leads to insufficient suppression of production. In obesity, it is triggered by enhanced lipolytic activity. The increase in visceral fat mass accompanied by an elevation of plasma free fatty acids (FFA) impairs insulin action and exacerbates insulin resistance via this mechanism (Reaven et al., 1988), which is a mechanism known as lipotoxicity (DeFronzo, 2004). High concentrations of FFA in skeletal muscle cells result in a decrease in intracellular glucose transport stimulated by insulin via the Glut4 transporter (Dresner et al., 1999 ), and in hepatocytes, an increase in gluconeogenesis and glucose release rate from the liver and an increase in insulin secretion from β cells in response to a transient increase in FFA or an inhibitory effect in response to chronic high levels (Boden, 1997). As a result of insulin resistance and lipotoxicity more insulin is required to induce glucose uptake from adipose and muscle cells, as well as glycogen synthesis in the liver (Cefalu et al., 2016). Excessive production of insulin by pancreatic β cells is a physiological response to insulin resistance and can lead to a decline in β cell function and ultimately prediabetes and type 2 diabetes (Donath et al., 2005). Genetic factors, age and lifestyle (overweight / obesity and inactivity) are risk factors for insulin resistance. Furthermore insulin resistance associated with type 2 diabetes is a cause of inadequate glycemic control and leads to failure of oral hypoglycemic agents (OHA) and ultimately the need to initiate insulin therapy . A 5–10% weight loss is associated with significant and clinically meaningful improvements in insulin sensitivity, glycemic control, hypertension and lipid abnormalities.

[0003]

[0004] ​​​ Lifestyle changes through dietary counseling and regular physical activity can lead to weight loss and blood sugar reduction. This is the first step toward control (Cefalu et al., 2016). Thus, aerobic exercise training stimulates glucose transport by insulin. To increase glycogen synthesis in muscles through increased transtransfer phosphorylation (Glut4). This improves insulin sensitivity in insulin-resistant patients (Persegh (in et al., 1996).

[0005] Treating obesity is difficult. Lifestyle interventions are clinical trials involving intensive counseling. While effective in terms of setting, it is difficult to adhere to and maintain, making it impractical in real life. It is not very effective. Drug therapy for obesity is limited, associated with side effects, and fat mass (FBM) This results in the loss of both lean body mass (LBM) and muscular fat (Heymsfield et al.) (2014). Weight loss studies consistently show that the loss of lean body mass accounts for about a quarter of the loss of body composition. This shows the results of a meta-analysis of a 26-person overweight or obese cohort with dietary and behavioral interventions. The analysis reported an average weight loss of >10kg. The analysis showed that the magnitude of calorie restriction was related to lean body mass. It was shown to be significantly associated (p=0.006) with the percentage of weight loss. The percentage change in lean body mass is (X±SD; 27±7%) in men compared to women (20±7%). The %) was larger (p=0.08) (Chaston et al 2007). Example For example, for every 1 kg of body fat lost during weight loss, postmenopausal women lose approximately 0.26 kg of body fat. Lean tissue was reduced (Chmelo et al 2016). Importantly, lean tissue was reduced. The loss of fat mass is only partially recovered with weight gain; that is, the body fat recovered in the following year. Only 0.12 kg of lean tissue was recovered for every 1 kg of fat lost, and this is because of the relationship between lean tissue and fat. This indicates a persistent negative balance (Chmelo et al 2016). Other studies have shown that as weight recovers, about half (45%) of total body fat mass recovers, but it does not decrease. This indicates that lean body mass did not recover. Obesity clinical trials reporting on the effects on body composition. This includes exercise in the form of aerobic exercise, and in terms of lean body mass loss, it was about 1 / 2 of the group on diet alone. A decrease of 2 was observed (Heymsfield et al 2014), which is due to the exercise regimen. The addition of [unclear] has shown that it can partially protect against the loss of lean body mass. There are no approved obesity interventions that promote fat loss while preserving or forming lean body mass.

[0006] Activin type 2 receptors (ActRIIA and ActRIIB, collectively abbreviated as ActRII) modulate signaling to ligands belonging to the transforming growth factor beta (TGF-β) superfamily, including myostatin, GDF-11, and activin. Myostatin, activin A, and GDF-11 are negative regulators of skeletal muscle growth, acting via the ActRII receptor signaling pathway to inhibit muscle protein synthesis and myocyte differentiation and proliferation. Preclinical reports in normal or high-fat diet mice show that increased muscle mass observed in either myostatin knockout mice or myostatin sequestration with soluble ActRIIB is associated with improved systemic insulin sensitivity, as measured by glucose and insulin loading tests and hyperinsulinic euglycemic clamp methods, as well as resistance to diet-induced and hereditary obesity (Guo et al, 2009; Akpan et al, 2009). Antibody-mediated inhibition of ActRIIB increases skeletal muscle mass through a mechanism that, while not fully understood, potentially involves the induction of brown adipose tissue activity. On the other hand , reducing white adipose tissue in mice on a normal or high-fat diet. do not have This was shown (Fournier et al 2012).

[0007] Bimaglumab (BYM338), a recombinant human monoclonal antibody, has a natural rigor. It binds competitively to ActRII with higher affinity than other drugs. Bimaglumab is suitable for treating muscle wasting. It is under development for symptomatic treatment and is available to healthy volunteers with sporadic inclusion body myositis (sIBM). In patients with sarcopenia, a significant increase in skeletal muscle mass has been observed. Previous studies have shown that a single dose of bimaglumab is more effective than placebo in healthy, lean adults. In humans, approximately 6% of the thigh muscle volume measured by magnetic resonance imaging after 10 weeks. It caused a % increase and reduced body fat mass to a similar extent (Roubenoff and Papanicolaou, New treatments for muscle wasting:an update on bimagrumab and othe (Summary from ICFSR 2015). Prediabetes due to overweight / obese individuals. In patients, a single dose of bimaglumab resulted in a maximum reduction of approximately 8% in body fat mass and approximately 3% This resulted in a significant impact on body composition, accompanied by an increase in lean body mass (DXA) (Garito T, Diabetes Obesity and Metabolism,2017) The net effect on total body weight was neutral. Insulin sensitivity was two steps higher. Measured using the euglycemic clamp method, an improvement of approximately 18% was observed. This effect is attributed to a 0.2% reduction in HbA1c. This is associated with an absolute decrease in c, which predicts progression to diabetes in similar populations. This is the magnitude of the effect related to prevention (DeFronzo et al 2011, Kn Owler et al. (2002). 10 mg / kg bimaglu every 4 weeks for 1 year. In patients with sporadic inclusion body myositis (sIBM) who received a total of 12 intravenous doses of mab: This resulted in a gradual decrease in body weight. At week 52, 10 mg / kg of bimaglumab was administered monthly. Patients who received the drug received an average of 270 grams compared to patients treated with placebo. 3.68 kg was lost; compared to a 750 gram loss in the placebo group, the average was 1 An increase of 0.6 kg in lean body mass; compared to 120 grams in patients treated with placebo. The average loss of fat mass was 5.05 kg (data not publicly available BYM338B2203). .

[0008] International publication no. 2013 / 006437 (Novartis AG) is a brochure about fertility. Regarding the treatment of metabolic disorders, including manure, this involves increasing brown adipose tissue and decreasing fat. This is related to its heat-generating activity as a mechanism, but when combined with an increase in lean body mass, the lipids... It is not associated with fat (white adipose tissue) loss. In BYM338X2206, it was statistically significant. However, there is a tendency towards beneficial effects of ActRIIB blockade on BAT activity. This is supported by preclinical data, as mitochondria in BAT This may be a result of activation of oxidative metabolism [Fournier et al., 2012]. Interestingly, preclinical studies have shown that intracellular triglycerides maintain BAT energy metabolism. Not only is it the main fuel for survival, but cold loads also lead to the near complete depletion of BAT lipids. It has been shown that this is possible [Ouellet et al., 2012]. In that case, this The mechanism is the contraction of BAT volume in response to bimaglumab treatment, which was also observed in this study. This could be the underlying reason. Significant results in BAT mass and activity of BYM338X2206 Due to its absence, research on this pathway was discontinued.

[0009] The treatment of obesity or overweight conditions and their associated comorbidities, particularly type 2 diabetes, is phase This represents the very medical needs that remain unmet. Therefore, in relation to body fat mass... By changing the ratio of lean body mass, body composition is improved, thereby leading to weight loss or central body mass. Drug therapy that can achieve a reduction in fat accumulation and improve the patient's blood glucose level is very This is desirable.

[0010] The current treatment involves the effects of bimaglumab on body composition and these on blood glucose parameters. To assess the metabolic effects of the changes, obese and overweight individuals with type 2 diabetes were subjected to a study. It is designed to achieve the loss of body fat mass associated with an increase in lean body mass, i.e., weight Neutral interventions suitably improve insulin sensitivity and blood glucose parameters, such as HbA1c. This involves evaluating whether someone is obese, overweight, or has a normal BMI. In humans, too, targeting fat loss such as central fat accumulation (obesity of the abdomen or trunk) This represents a model of the strategy. [Overview of the project] [Means for solving the problem]

[0011] The present invention relates to myostatin or activin, their receptor ActRII (preferably) This refers to ActRIIB and ActRIIA, or ActRIIA or ActRIIB. By sufficiently blocking binding to either of the receptors (or both), skeletal muscle growth acting on the receptor is inhibited. The activity of myostatin and other ligands is significantly reduced, while the activity of these ligands Some can perform other physiological functions via alternative type II receptors (Up This is based on the treatment approach described by ton et al (2009). Myostatin Other approaches to reduce activity include competitive solubility that creates a soluble receptor sink. ActRII depletes a range of ActRII ligands that are active in other receptors. This may be possible, and is more effective than using receptor antagonist antibodies like bimaglumab. This could potentially create safety risks.

[0012] As a potent inhibitor of ActRII, bimaglumab is used in conjunction with myostatin and activin A. The action of GDF11, and possibly other ligands that act through these receptors. Block it.

[0013] Therefore, this disclosure relates to myostatin or activator for use in improving body composition. A tibin antagonist or receptor antagonist, preferably a myostatin-binding molecule The antibody, more preferably an anti-ActRII receptor antibody, and most preferably bimaglumab, is provided. To provide.

[0014] Therefore, this disclosure is for use in the treatment of obesity or overweight conditions, myosta A tin or activin antagonist or receptor antagonist, preferably myostat A tin-binding molecule or antibody, more preferably an anti-ActRII receptor antibody, most preferably a vi We offer MaguruMab.

[0015] In a similar manner, the present disclosure improves body composition, thereby increasing lean body mass and body fat. Myostat, for use in the treatment of obesity in patients, due to a reduction in fat mass or activin receptor antagonists, preferably myostatin receptor antagonists Preferably myostatin or an activin-binding molecule or antibody, more preferably This provides an anti-ActRII receptor antibody, most preferably bimaglumab.

[0016] In a similar embodiment, the present invention relates to the treatment and prevention of comorbidities associated with obesity or overweight conditions. Alternatively, for use in mitigation, an activin antagonist, preferably an anti-ActRI We provide an I receptor antibody, most preferably bimaglumab.

[0017] In a further embodiment, the present invention relates to blood glucose control in patients with type II diabetes For use in the field, an activin antagonist, preferably an anti-ActRII receptor The present invention provides an antibody, most preferably bimaglumab.

[0018] The present invention further relates to myostatin receptor antagonists for use herein. This document provides specific administration regimens for maglumab.

[0019] The present invention will be described in detail below with reference to the attached drawings. [Brief explanation of the drawing]

[0020] [Figure 1-1] Figure 1: Change from baseline in body composition as assessed by DXA. Data are provided as arithmetic mean (SE). A: Lean body mass. B: Fat mass. [Figure 1-2] (As stated above.) [Figure 2] Insulin concentration versus time during IVGTT in patients who visited the clinic and those who received treatment. Data are provided as arithmetic mean (SE). [Figure 3] Individual percentage changes from baseline fat mass to M / I as measured by DXA in Steps 1 and 2. Panels A and B show a linear and significant relationship between body fat mass loss and increased insulin sensitivity for Steps 1 and 2. Individual percentage changes from baseline lean body mass to M / I as measured by DXA in Steps 1 and 2. In both Step 1 (C) and 2 (D), there appears to be no relationship between the change in lean body mass and insulin sensitivity. [Figure 4] Absolute change in HbA1c from baseline over time. Data are provided as arithmetic mean (SE). [Figure 5] Arithmetic mean (SD) concentration-time plots based on treatment. Pharmacokinetic analysis shows a non-linear clearance profile. [Figure 6] The clinical trial design is shown. [Modes for carrying out the invention]

[0021] The present invention will be described and illustrated in more detail below.

[0022] This disclosure provides the following embodiments.

[0023] 1. It increases lean body mass and decreases body fat mass, and is used in improving body composition in human subjects. Myostatin, activin, or activin receptor antagonist.

[0024] 2. Central fat accumulation in human subjects who are obese, overweight, or have a normal BMI. Myostatin or activin or activin receptor anthracite for use in treatment Gonist.

[0025] 3. The patient weighs 30 kg / m². 2 The use described in Embodiment 1 or 2, having the above BMI Myostatin or activin or activin receptor antagonist for use.

[0026] 4. The patient weighs 25 kg / m². 2 More than 30kg / m 2 Embodiment 1, having a BMI of less than or myostatin or activin or activin receptor for use as described in 2. An antagonist.

[0027] 5. The patient weighs 25 kg / m². 2 A user having a BMI less than 1, as described in Embodiment 1 or 2 Myostatin or activin or activin receptor antagonist for use.

[0028] 6. Central fat accumulation is reduced, and the use described in any of Embodiments 1 to 5 is reduced. Ostatin, activin, or activin receptor antagonist.

[0029] 7. Use in the treatment, prevention, or reduction of obesity or overweight conditions and associated comorbidities. Myostatin or activin or activin receptor antagonist for this purpose.

[0030] 8. Comorbidities associated with obesity or being overweight include type 2 diabetes, glucose intolerance, and preglycerides. Diabetes, insulin resistance, high triglycerides, physical disability, osteoporosis, kidney disease, obstructive sleep disorders Endocrine disorders such as sleep apnea, sex hormone disorders, polycystic ovary syndrome, or male hypogonadism. Reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, brain A selection from the group of stroke, gallstones, and changes in the gonadal hormone profile, as described in Embodiment 7. Myostatin or activin or activin receptor antagonist for use.

[0031] 9. Use of the embodiments described in Embodiments 7-8 for the treatment, alleviation, or prevention of type II diabetes Myostatin, activin, or activin receptor antagonist.

[0032] 10. The use described in Embodiments 7-9, in which the improvement of body composition includes the reduction of central fat accumulation. Myostatin, activin, or activin receptor antagonist.

[0033] 11. Embodiment 1 for the prevention of type II diabetes and the treatment of obesity or overweight conditions Myostatin or activin or activin receptor antagonist for use as described in 0. Nist.

[0034] 12. Antagonist of Embodiment 11 for use in improving blood glucose control For use as described above, myostatin or activin or activin receptor antagonist St.

[0035] 13. Improved blood glucose control is achieved through improved insulin sensitivity; implementation details For use as described in Form 12, myostatin or activin or activin receptor annealing Tagonist.

[0036] 14. For use in patients with type II diabetes to improve blood glucose control. Myostatin or activin or activin receptor antagonist.

[0037] 15. Improved blood glucose control is achieved through improved insulin sensitivity, implementation details For use as described in Form 14, myostatin or activin or activin receptor annealing Tagonist.

[0038] 16. Use according to Embodiments 14-15 when the patient is obese or overweight. Myostatin or activin or activin receptor antagonist for this purpose.

[0039] 17. DTSQ score (Diabetes Treatment Satisfaction Questionnaire score, or IWQOL / IW QOL-lite (Effect of Weight on Quality of Life) score or obesity The use described in Embodiment 16 improves other PROs related to diabetes. Myostatin, activin, or activin receptor antagonist.

[0040] 18. Myostatin or activin antagonist is an anti-ActRII receptor antibody. or myostatin or activin or for use as described in any of the preceding embodiments Activin receptor antagonist.

[0041] 19. The use described in Embodiment 18, wherein the anti-ActRII receptor antibody is bimaglumab. Myostatin or activin or activin receptor antagonist for this purpose.

[0042] 20. Bimaglumab is administered at a dose of 3 mg / kg or 10 mg / kg. myostatin or activin or activin for use as described in Embodiment 19 Receptor antagonist.

[0043] 21. The use of the embodiment described in Embodiment 20, in which bimaglumab is administered every four weeks. Myostatin or activin or activin receptor antagonist for this purpose.

[0044] 22. A method for improving body composition in a patient who requires it, thereby eliminating Fat mass increases and body fat mass decreases, myostatin or activin antagonist or A method comprising administering an activin receptor antagonist.

[0045] 23. A method for treating central adipose tissue accumulation in patients who require it, wherein the subject is Obese, overweight, or with a normal BMI, myostatin or activin anthate A method comprising administering a gonist or activin receptor antagonist.

[0046] 24. The aforementioned patient weighs 30 kg / m². 2 Embodiments 22 or 23, which have the above BMI, are described below. Instructions for handling the contents.

[0047] 25. The patient weighs 25 kg / m². 2 More than 30kg / m 2 Embodiments having a BMI of less than The treatment method described in 22 or 23.

[0048] 26. The patient weighs 25 kg / m². 2 The BMI of less than the BMI of Embodiment 22 or 23 Instructions for handling the contents.

[0049] 27. A treatment method according to any one of embodiments 22 to 26, which reduces central fat accumulation. .

[0050] 28. Myostatin or activin antagonist or activin receptor antagonist Treatment and prevention of comorbidities associated with obesity or overweight conditions, including the administration of nistrone. This is a method of mitigation.

[0051] 29. Comorbidities associated with obesity or being overweight include type 2 diabetes, glucose intolerance, and pre- Diabetes, insulin resistance, high triglycerides, physical disability, osteoporosis, kidney disease, obstructive sleep disorders Internal conditions such as sleep apnea, sex hormone disorders, polycystic ovary syndrome, or male hypogonadism. Reproductive disorders, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, brain As described in Embodiment 28, selected from the group of stroke, gallstones, and changes in the gonadal hormone profile. The method.

[0052] 30. Methods for treating, preventing or alleviating type II diabetes according to embodiments 22 to 29.

[0053] 31. Myostatin or activin antagonist or activin receptor antagonist Improvement of blood glucose control in patients with type II diabetes, including the administration of nistrone. Good method.

[0054] 32. Improved blood glucose control is achieved through improved insulin sensitivity; implementation details The method described in state 31.

[0055] 33. The method according to Embodiments 30-32, wherein the patient is obese or overweight. .

[0056] 34. DTSQ score (Diabetes Treatment Satisfaction Questionnaire score), or IWQOL / I WQOL-lite (Effect of Weight on Quality of Life) score or obesity Any of embodiments 28-33, in which other PROs related to diabetes are improved. The method used.

[0057] 35. Myostatin or activin receptor antagonists are anti-ActRII receptor antagonists. The method according to any of the above embodiments.

[0058] 36. The method according to embodiment 36, wherein the anti-ActRII receptor antibody is bimaglumab.

[0059] 37. Bimaglumab is administered at a dose of 3 mg / kg or 10 mg / kg. The method according to embodiment 37.

[0060] 38. Bimaglumab is administered every four weeks, as described in Embodiments 37-38. The method.

[0061] Alternatively, according to Embodiment 39, bimaglumab is administered in doses of 210 mg or 700 mg. It is preferably administered every four weeks.

[0062] In the above embodiment, a patient with type 2 diabetes is treated with background antidiabetic therapy. According to either source, the approved treatment is either monotherapy or in combination with insulin. It is an antidiabetic drug.

[0063] This disclosure also relates to treating diseases or conditions according to any of the embodiments 1 to 39 described above. For manufacturing pharmaceuticals, myostatin or activin according to any prior embodiment Use of agonists (administration, administration regimen, administration interval, and specific patients and endogenous zones) (Including the int.)

[0064] This disclosure also relates to myostatin or activin antagonists according to any prior embodiment. Treatment methods including administration (administration, administration regimen, administration interval, and specific patients and adults) Includes (including points).

[0065] Within the scope of this disclosure, any embodiment, method or use may be combined with one another. Cut.

[0066] Muscle regulation and ActRII receptors Transylamine containing myostatin, activin A, and growth differentiation factor 11 (GDF11) Some members of the Forming Growth Factor Beta (TGF-β) superfamily are It negatively regulates skeletal muscle mass in animals and humans throughout the life cycle. Signaling occurs via the type II activin receptor (ActRIIA and B) Both; as well as primarily the Smad2 / 3 pathway), muscle protein synthesis and muscle cell differentiation and It inhibits proliferation. In animal and human development, none of these ligands are present. This results in a hypermuscular phenotype with an increase in the number and size of muscle fibers. When myostatin levels decrease, skeletal muscle hypertrophy occurs due to an increase in the size of existing muscle fibers. Large amounts occur (Lee et al 2005; Lee et al 2010; Tren (Delenburg et al 2012). Therefore, at the receptor level, this signal The ability to regulate muscle growth by perturbing the TGF-β signaling pathway is much greater than previously recognized by direct anti-myostatin approaches.

[0067] Bimagrumab Bimagrumab, a pharmaceutically active compound used according to the present invention, is an activin receptor type II (ActRII) that was developed to competitively bind with a higher affinity than natural ligands that limit muscle mass gain, including myostatin and activin. It is a fully human monoclonal antibody (modified IgG1, 234-235-Ala-Ala, λ2). Bimag rumab is cross-reactive with human and mouse ActRIIA and ActRIIB and is effective with respect to human, cynomolgus monkey, mouse and rat skeletal muscle cells. Bimagru mab binds to human ActRIIB with extremely high affinity (KD 1.7 ± 0.3 pM) and with relatively low affinity (KD 434 ± 25 pM) to human ActRIIA and is formulated for intravenous (i.v. ) administration.

[0068] The production of bimagrumab is described in WO 2010 / 125003 pamphlet .

[0069] Bimagrumab contains an antigen-binding site that includes at least one immunoglobulin heavy chain variable domain (V ) that includes CDR1 of SEQ ID NO:1, CDR2 of SEQ ID NO:2, and CDR3 of SEQ ID NO:3 in the hypervariable region of the sequence. H

[0070] The use of an antibody having changed 1, 2 or 3 residues from the sequence of any of the CDR1, CDR2 and / or CDR3 of the heavy chain is also included within the scope of the present invention.

[0071] Bimaglumab is also known as CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and SEQ ID NO: At least one CDR3 of 6, or its CDR equivalent, included in the hypervariable region of the array Immunoglobulin light chain variable domain (V L It contains an antigen-binding site including ). CDR1 of the light chain, It has 1, 2, or 3 residues that have been modified from either the CDR2 and / or CDR3 sequence. The use of antibodies is also included within the scope of this invention.

[0072] Bimaglumab also contains the light chain of SEQ ID NO: 7 or SEQ ID NO: 8 and the heavy chain of SEQ ID NO: 9. nothing.

[0073] According to the present invention, the use of an antibody having 95% identity with the light chain and / or heavy chain is also included. It can be done.

[0074] The sequence listing for bimaglumab is provided herein.

[0075] Clinical trial design. Clinical trial CBYM338X2206 ran from August 21, 2012 to October 25, 2014. Clinical Research, Chula Vista, California An exploratory Phase Ib, randomized, double-blind, placebo-controlled, single-center study conducted at Inc. This was a single-dose trial. Sixteen healthy volunteers with insulin resistance were tested. Participants were randomly assigned in a 6:1 ratio to receive bimaglumab 30 mg / kg intravenously over approximately 2 hours. A single intravenous injection or placebo was administered, followed by a 4-hour observation period. A 24-week follow-up was conducted after the treatment period. All subjects throughout the study period You will be instructed to maintain your current (at the time of screening) level of physical activity and motor behavior. The primary endpoint was bimaglumab's effect on systemic insulin sensitivity and body composition. The objective was to determine the effect. Patients were assessed at baseline and 10 weeks after drug treatment (7th week). The patient was evaluated on day 1 and followed up for 24 weeks. This clinical trial was conducted by ICH Har monized Tripartite Guidelines for Good C In line with the clinical practice, applicable local regulations, and the Helsinki Declaration Designed in accordance with established ethical principles. The clinical trial protocol and all modifications are in the United States. , 33323, Florida, Sunrise Facility has an independent facility review board (I Reviewed by RB.

[0076] Target population: Adult men and women aged 18-65 who provided informed consent. Elephants were included in the clinical trial. Other selection criteria included a body mass index (BMI) of 18-45 kg / m². 2 , oyo Blood glucose levels 140-199 mg / dl 2 hours after administration of 75g oral glucose (OGTT) Alternatively, it can be defined by homeostasis model assessment - insulin resistance (HOMA-IR) of 2.6 or higher. The diagnosis was glucose intolerance. The calculation is as follows: HOMA-IR=empty Abdominal blood glucose (mg / dL) × Fasting insulin (mU / L) / 405. The main exclusion criteria are: All diseases, especially diabetes, testosterone, growth hormone, systemic glucocorticoid therapy She was a patient under the law and a woman of childbearing potential.

[0077] Hyperinsulinic euglycemic clamp method. (Le et al, 2009) Standardized dinner Following the intake of (10kcal / kg; 50% carbohydrates, 30% fat, 20% protein) After fasting for at least 12 hours overnight, the subjects were given Biostator (Indiana, USA). It was connected to Elkhart (Life Science Instruments). I placed one hand under the heating pad to allow for the collection of arterial and venous blood. To maintain blood glucose levels at the target level of 90 mg / dL, insulin should be 1 mU / kg-1 Intravenous infusion was administered at a rate of 0.min-1 for 180 minutes (Step 1). After 180 minutes, another 1 Increase the insulin infusion rate to 2.5 mU / kg-1 min-1 for 80 minutes (step 2) Steady-state hyperinsulinemia was sufficient to prevent hepatic glucose excretion. Insulin infusion was discontinued at the end of Phase 2. It was necessary to maintain blood glucose levels at 90 mg / dL. The required 20% v / v glucose infusion rate (glucose infusion rate, or GIR) (mg. (kg-1.min-1) throughout the euglycemic hyperinsulinic clamp period, especially during both periods. The last 30 minutes (in a quasi-steady state) were recorded (steps 1 and 2). GIR is the ins It was used to calculate the phosphorus sensitivity index (i.e., M, M1, S1). Insulin sensitivity measurement The steady-state period for determination is 150-180 minutes in steps 1 and 2. Defined. The total duration of the two-step HE clamp procedure was approximately 7 hours. Serum insulin Blood samples for measuring 0, 150, and 1 in step 1 are used to measure the glucose and glycation concentrations. After increasing to a higher insulin infusion rate in Step 2, at 60, 170, and 180 minutes. Samples were collected at 150, 160, 170, and 180 minutes.

[0078] IVGTT. After a minimum of 8 hours of overnight fasting, subjects were subjected to evaluation of phase I insulin release. I underwent an intravenous glucose tolerance test. My basal blood glucose levels were measured for glucose and insulin. Samples were taken at -5 minutes and 0 minutes. At 0 minutes, a glucose bolus containing 0.3 g / kg body weight was used. The drug was administered as D50 (50% solution in sterile water). Bolus delivery was completed within 2 minutes. Blood samples were taken at 2, 4, 6, 8, 10, 15, and 20 minutes, and then cannulated. -Removed.

[0079] PET FDG-18 / CT scan for BAT evaluation. Baseline and first In week 0, all subjects were subjected to "cold" exposure and "warm" (or thermally neutral) conditions. , radioactive 18 Positron emission tomography using fluorodeoxyglucose (FDG) PET was performed (Virtanen KA et al, 2009). Under cold exposure. BAT activation is performed in a room adjacent to the scanner room, with an ambient temperature set to 17-18°C. This was achieved over an hour by cooling the subject while wearing thin clothing. PET During the CT scan itself, the scanner room temperature is set to 17-18°C to maintain cold exposure. The scan obtained under warm conditions (temperature of 22-24°C) was compared to the scan obtained under cold conditions. The scans were performed the day before or the day after the procedure. All scans were obtained under overnight fasting conditions. Shoulder region Immediately after dynamic acquisition, the lower limbs were scanned to show the gastrocnemius muscle as an example of fast-twitch and slow-twitch muscle tissue. The soleus muscle was imaged. PMOD software was used to image each voxel and the aorta. PET images were quantified using time-activity curves and a 128×128×63 matrix. Imaging of body metabolic rate measurements at micromolar glucose / 100g / min within the body, The expected values ​​were 5-15. We compared PET scans obtained under "cold" and "warm" conditions. This allowed quantitative measurements to be extracted from each dataset.

[0080] DXA scan. (Albanese et al, 2003) All subjects were concentrated. Can analysis (Novartis CRO) showed baseline, week 6, week 10, and week 14. Whole-body dual-energy X-ray absorptiometry (DXA) scans completed in week 1 and week 24 I received it. All scans require the subject to lie face up on the DXA table, and the carrier A blunt phantom was used to ensure consistency of DXA readings. These skims From Chan, absolute values ​​and baseline values ​​of lean body mass (LBM) and fat body mass (FBM). The relative change from was calculated. The test took 1-2 minutes. The effective dose of the DXA whole-body scan was calculated. The reading was 2.1 μSv.

[0081] Statistical analysis. Data analysis was conducted under the direction of Novartis staff. High insulin We analyzed pharmacodynamic (PD) variables (M / I) evaluated from the normal glucose clamp method to determine the target. Endpoints are changes from baseline values, and these endpoints are analyzed separately. Before the analysis, a logarithmic transformation was applied to each endpoint. Logarithmic transformation relative to baseline. The converted ratios were used for treatments (bimaglumab and placebo) as fixed effects and covariates. The analysis was performed using the ANCOVA model with log baseline values ​​as the basis for treatment estimation. Values, contrast of treatment differences (bimaglumab-placebo), and corresponding inverse 90% confidence intervals. The corresponding 90% confidence intervals were used, along with the corresponding percent relative to baseline for treatment comparison. Placebo-adjusted percentages were provided for the baseline and raw values. Descriptive statistics of the percentage and absolute change from baseline of the PD variable are available at time and processing. Provided by group and step. AUC (Area Under Curve) and Cmax (Maximum Value) are The glucose and insulin profiles were derived using IVGTT. HbA 1c , fasting insulin and glucose for the same period, DXA parameters and body The heavy data were analyzed separately using a mixed-effects model for repeated measures. All values ​​were changes from baseline. DXA parameters and weight were logarithmically transformed. The ratio, as well as the change from baseline, were treated as fixed factors (bimaglumab and planar). (Sev), visit and visit × treatment interaction, log baseline / baseline as covariate. The analysis was performed using the ANCOVA model with the target as the random factor and the value of the treatment. Values, contrast of treatment differences (bimaglumab-placebo), and corresponding inverse 90% confidence intervals. The corresponding 90% confidence intervals were used, along with the corresponding percent relative to baseline for treatment comparison. Placebo-adjusted percentages were provided for both the target and baseline.

[0082] result The clinical trial population. The healthy volunteers enrolled in this trial were primarily Caucasian (94%). , male (81%), and overweight or obese (average BMI 29.3 kg / m²) 2 Range: 2 1.1–37.7, median 28.6 kg / m 2 ) was the case. All subjects had a score of 2.6 or higher. Insulin resistance as defined by HOMA-IR, not diabetes, and average Hb A 1c The rates were 5.49% (±0.39) in the bimaglumab group and 5% (±0.39) in the placebo group, respectively. The rate was 0.35% (±0.24). A total of 16 subjects were enrolled and were in the bimaglumab group. There were 10 people in the bimaglumab group and 6 in the placebo group. The average age was 42.2 years in the bimaglumab group compared to 6 in the placebo group. Except for the placebo group being slightly older at 47.3 years old, both groups had similar baseline characteristics. They were equivalent in this regard. All baseline laboratory findings were equivalent.

[0083] Changes in body composition. Measured by dual-energy X-ray absorptiometry (DXA) scanning. A significant treatment effect of bimaglumab was observed in body composition at week 10. Total lean body mass (LBM) increased with bimaglumab (mean 2.7% at week 10 [90 [% confidence interval (CI) 0.45, 5.01; p=0.049] (Figure 1A), the treatment effect was, It was observed as early as week 6 (the first scan after administration) and continued until the end of the trial (week 24). There was a tendency towards baseline. Furthermore, compared to placebo, the bimaglumab group Then, a significant decrease in total body fat (FBM) was observed in week 10 (mean -7.9%). [90% CI -12.5, -3; p=0.011]), this effect was already observed in week 6 (first Observed in post-administration scans, and persisted until the end of the trial (average -6.5% at week 24 [9]). 0%CI -11.2, -1.5; p=0.034) (Figure 1B). Interestingly, L The effect of bimaglumab on BM reached a plateau level after 6 weeks and was observed in FBM. Compared to a sustained decline, there was only an increase of about 1% between week 6 and week 14. Throughout the study, there was no significant impact on body weight in any group compared to baseline. In week 10, the absolute increase in LBM due to bimaglumab was 750g (±2) in the placebo group. The average loss was 2 kg (±1.4 kg) compared to 0.1 kg, and the absolute loss of FBM was bimaglu The average weight loss was 2.3 kg (±1.7 kg) with Mab and 470 g (±0.7 kg) with placebo. Ta.

[0084] Insulin sensitivity and HbA 1c Insulin sensitivity is two steps higher than normal insulin sensitivity. Measured by the glucose clamp method, and adjusted for serum insulin levels (I) It was reported as a ratio to phosphorus sensitivity (M). Compared to insulin sensitivity (M / I) at week 10. The efficacy of bimaglumab treatment was 21.8% per step [90% CI -8.9]. 62.7; p=0.250], 18.2% per step 2 [90% CI -7.4, [50.9; p=0.247] showed an increase. Insulin sensitivity also showed an increase in intravenous glucose. The effect was evaluated by a glucose tolerance test (IVGTT). The effect of bimaglumab treatment at week 10 was evaluated by glucose It showed a significant decrease in the insulin response to insulin loading, and there was no therapeutic effect on blood glucose levels. The area under the curve (AUC) for insulin decreased by 38% [90% CI -52.6, -1 9; p=0.008], the maximum insulin concentration (Cmax) decreased by 30.4% [90 [%CI -48.7, -5.6; p=0.056](Figure 2). In the bimaglumab group, placebo No difference in fasting plasma glucose was observed compared to the B group (p=0.674), while in the P group... In the sebum group, there was a significant decrease in glucose AUC compared to the bimaglumab group (10.3%, p= A value of 0.011 was observed. The hyperinsulinic euglycemic clamp method showed loss of body fat mass and insulin A linear and significant relationship was observed between increased phosphorus sensitivity and (p=0 for step 1). 041, p=0.028 for step 2), on the other hand, changes in lean body mass and insulin sensitivity No such correlation was observed with sex (p=0.982 for step 1). In step 2, p = 0.411) (Figure 3). HbA 1c Treatment effect of bimaglumab This was observed as early as week 6, showing a decrease of 0.22%, [90%CI -0.31, -0. 12; p < 0.001], this persisted until the end of follow-up at week 24 (mean -0.24%) [90%CI -0.33, -0.14; p<0.001] (Figure 4). In the racebo group, HbA1c levels were elevated around week 18. 1c It showed a slow deterioration (mean 0.11%) [CI [90% -0.01, 0.24; p=0.144], but not statistically significant.

[0085] Brown adipose tissue (BAT). The heat-generating capacity of BAT is at neutral ambient temperatures (i.e., "warm"). Measurements taken at 22-24°C and at the end of 90 minutes of cold exposure (i.e., "cold" 17-18°C). It is defined by the difference in the defined glucose metabolic rate (ΔGMR). Treatment with bimaglumab Before placement, this cold load caused the GMR to increase from 0.56±0.15 μmol / 100g / min The concentration increased to 0.67 ± 0.24 μmol / 100g / min (+19%, N=15, p=0). 12). At 10 weeks after drug administration, the placebo group showed a decreasing trend in fever response, and such Progression to further impairment of BAT activity was not observed in the bimaglumab group (ΔGMR). [寒冷-温暖] Placebo: -0.23±0.27 μmol / min, vs. BYM338: 0.06 (±0.35 μmol / min, p=0.11). The decreasing trend in BAT levels was also observed in week 10. This was also observed in the maglumab group, while no effect on BAT levels was detected in the placebo group. (BYM338: -36.9±44.8mL, vs. placebo: -4.7±18.8mL, p (=0.12).

[0086] Muscle strength. The therapeutic effect of bimaglumab on muscle strength as measured by the leg press is 1 33% at 4 weeks [90% CI -5.5, 87.1; p=0.168], and at the end of the study (2nd At 4 weeks, there was a 45.3% increase [90% CI 3.3, 104.4; p=0.073]. This trend was observed. These effects did not reach statistical significance.

[0087] Pharmacokinetics. The pharmacokinetics of bimaglumab in overweight and obese individuals are different from those in lean and obese individuals. This is consistent with observations made in low-body weight individuals, with a threshold of approximately 10 μm for nonlinear clearance loss. The targeted-medium-drug-kinetic (TMDD) profile in g / mL is shown (Figure 5). Loss of clearance may be associated with loss of receptor saturation, at 30 mg / kg A single dose is administered until week 10, when the therapeutic effect on body composition and insulin sensitivity is demonstrated. (71 days) It appeared to saturate the receptors.

[0088] Adverse events. During this clinical trial, serious adverse events (SAEs) and adverse events that could lead to discontinuation of the trial occurred. There were no adverse events (AEs). Acne, muscle cramps, and muscle pain were observed in patients treated with bimaglumab. It was reported in 30% of the population, but not in the placebo-treated group. Diarrhea, muscle weakness, Musculoskeletal rigidity was observed in 10% of the bimaglumab group but not in the placebo group. Upper respiratory tract infections were one of the most frequently reported AEs, but they were not related to the investigational procedure. It was not suspected that this was the case. Anti-drug antibodies (ADAs) were present in 2 out of 10 people after exposure to bimaglumab. It was detected in human subjects and was not neutralized by either ActRIIA or ActRIIB. These ADAs were not associated with unfavorable safety findings or changes in drug exposure. It wasn't there.

[0089] Consideration A single dose of bimaglumab is clinically significant in insulin-resistant, non-diabetic individuals. HbA 1c This resulted in decreased insulin sensitivity. In the absence of significant weight loss or lifestyle changes, these metabolic effects of bimaglumab are: It was associated with significant changes in body composition. The Look AHEAD trial showed that body weight increased by 5-1% over one year. Demonstrating that a 0% weight loss induces clinically significant improvement in cardiovascular risk factors, and preventing diabetes The program (Diabetes Prevention Program) reduces by 5% The amount was shown to reduce the 5-year risk of developing new type 2 diabetes by 58% (Diabete s Prevention Program Research Group,2002 Risk reduction is associated with a decrease in visceral fat mass in response to these combined interventions. Obtained. A single dose of bimaglumab showed a significant improvement in total LBM of 2.7% (2 kg ± 1.4). This leads to an increase, while a weight loss regimen with a normal protein intake (1.2g / kg / day) Even with added exercise, the total LBM will at best only maintain the baseline level, while lean body mass will not decrease. No increase has been shown (Longland et al., 2016). Furthermore, Vimag Lumab resulted in a significant and sustained reduction in total FBM of 7.9% (2.3 kg ± 1.7) at week 10. This combination effect results in less resistance, and to the best of our knowledge, it has been found to be effective against any other type of resistance to date. This was not observed with obesity medications. The net result of these changes is a significant reduction in body fat accumulation. In other words, it is a neutral weight-bearing effect combined with a reduction in the proportion of body fat in soft tissue mass. This resonates with a healthier and more robust body composition. Insulin sensitivity, and therefore The metabolic impact of these body composition changes on blood glucose parameters is relevant to insulin resistance. It was significant even in heterogeneous groups. Thus, bimaglumab is metabolically effective in reducing fat accumulation. It possesses a novel mechanism for addressing change. Obese patients, especially those with internal obesity / fat accumulation. In patients, especially when combined with a calorie-restricted diet, bimaglumab A sustained increase in lean body mass due to longer-term treatment also leads to a continuous relative decrease in tissue fat accumulation. Further clinical trials are needed to investigate whether it can promote the associated weight loss.

[0090] Since no effect was observed on fasting blood glucose levels, HbA 1c Improvement is likely due to postprandial blood glucose levels This is thought to reflect a decrease in peripheral insulin sensitivity. The effect on postprandial blood glucose levels is increased peripheral insulin sensitivity. May reflect the addition. HbA 1c The observed conversion of the treatment effect on the decrease was metformin. or higher than what was achieved through lifestyle interventions (HbA1c in 5 months) 1c (Approximately a 0.1% decrease) (Diabetes Prevention program Research Group (OUP, 2002), this was observed in a similar population with liraglutide 3.0 mg qd. It is equivalent to the result obtained (HbA1c decreased by 0.23% in week 56) (Pi-Sunye) (r et al, 2015). Hyperinsulinic euglycemic clamp method and IVGTT The effect of bimaglumab on insulin sensitivity, as measured by the indicators used, is Although there are slight differences among the three clinical trials, similar calorie-restricted PIOGs in the same population. The effect is equivalent to that of ritazon (45 mg) and liraglutide (1.8 mg) (DeFr onzo et al.,2011;Kim et al.,2013;Matsuda et al, 1999). When administered to a more homogeneous group of patients with insulin-resistant type 2 diabetes... In addition, to investigate whether long-term treatment with bimaglumab is more effective. Further, larger-scale clinical trials are needed.

[0091] In this new population, primarily consisting of overweight and obese individuals, bimaglumab is generally safe. It was well-tolerated, and no major safety concerns were observed. Adverse events were mild and transient. Previous clinical experience with bimaglumab, namely acne (especially at the dose level used in this study) In the case of (in The biological explanation for acne remains unclear and is being further investigated.

[0092] The main findings from this study with a short treatment period were a rapid increase in lean body mass and a decrease in body fat mass. This combination includes a significant reduction in body fat accumulation without a change in weight. These changes can alter body composition without the use of physical exercise and dietary restrictions. This led to a shift to the "fit-fat" phenotype.

[0093] Furthermore, these changes in body composition without weight loss can lead to visceral damage to blood glucose parameters. This reflected the metabolic effects of weight loss accompanied by [unclear].

[0094] The limitation of this clinical trial is the fact that it is an experimental, exploratory trial involving a small number of participants. This includes the body mass index (clinical trials included people of normal weight, overweight, and obese individuals) and The population was heterogeneous in terms of body fat distribution. Therefore, insulin sensitivity and HbA1c 1c The evaluation of the magnitude of the effect of bimaglumab on body fat was limited. In this clinical trial, The effect of bimaglumab on various compartments of (body fa) was not evaluated, and Since this could not be done, the effects on the fat content of the internal organs, subcutaneous tissue, and liver were not determined. This cannot be discussed. The observed mechanism of improved insulin sensitivity has not been systematically studied. It has not been thoroughly investigated, and there is a difference between insulin sensitivity (M / I) measured by FBM and clamp. An unexpected relationship was observed (which was not observed in LBM), so this is intramuscular fat. Decrease in volume (Kuhlmann et al, 2003), and / or overall body fat mass This may be followed by a decrease (Figure 3). Furthermore, it may also be an increase in circulating adiponectin. This may include the initial study of repeated doses of bimaglumab in healthy volunteers. This was observed in clinical trials.

[0095] Recent treatment with bimaglumab 10 mg / kg administered for at least 6 months Clinical trials have shown that the effect on skeletal muscle mass (hypertrophy) tends to reach its maximum after 2-3 months of treatment. However, the effect on body fat mass increases with longer-term treatment, ultimately leading to increased muscle mass. It was demonstrated that the magnitude of the increase was greater than that, thereby promoting weight loss. Furthermore, DEXA Local measurements showed that the main portion of body fat loss came from the trunk, specifically from the subcutaneous tissue. It includes both fat mass and visceral fat mass. Conventional DEXA does not distinguish between these two components. Although this cannot be determined, this observation does not rule out the possibility of a potential involvement of visceral fat accumulation. There is no such effect. The effects of these bimaglumab-treated long-term treatments on trunk fat volume are central adipose tissue. It is particularly beneficial for patients with the following conditions (typically insulin resistance and type 2 diabetes): If so, how does this affect insulin sensitivity and metabolic profile? And ultimately clinically meaningful HbA 1c To clarify whether this will lead to an improvement in the decrease Therefore, further improvements are being made using more advanced imaging technologies (such as whole-body CT or MRI). Large-scale clinical trials are needed.

[0096] The contribution of increased hepatic insulin sensitivity to the observed beneficial effects of bimaglumab is unknown. It has not been found. However, in line with preclinical observations regarding anti-myostatin antibodies, Vimag Previous studies on lumab have shown a dose-dependent increase in circulating adiponectin levels. In addition to conferring insulin sensitivity to skeletal muscle, adiponectin also improves liver function. Fatty acids with known direct effects in the liver that can confer insulin sensitivity This is a hormone. The inventors have found that the amount of tissue fat accumulation in skeletal muscle is reduced (intramuscular fat mass) (Due to an increase in lean body mass combined with a decrease in muscle mass) and a reduction in systemic and local inflammation, This leads to improved contractility, thereby improving the functionality and mobility of these individuals. I am speculating that the effect of the one-legged leg press on muscle strength suggests a trend, Due to the small sample size and heterogeneity among participants, the results were not conclusive. To study this problem in a more focused way, we will use a larger sample size. Further clinical trials are needed. In conclusion, bimaglumab is used to treat metabolic obesity such as insulin resistance. It may offer a new approach to managing sexual complications. Bimaglumab may affect body composition. Significant effects and novel insulin for type 2 diabetes through increased adiponectin It may potentially be a phosphate sensitization treatment. It tends to increase body weight and body fat mass. Unlike the available treatments for type 2 diabetes, bimaglumab targets central adipose tissue, This could potentially overturn important characteristics of the underlying pathophysiology of type 2 diabetes.

[0097] Example 2: Research Plan Clinical trial design BYM338X2211 is used for intravenous bismaggur in overweight / obese patients with type 2 diabetes. A non-verbal, randomized, subject- and principal investigator-investigated study of a 48-week treatment period with B. This was a blinded, placebo-controlled, parallel-group trial. Approximately 60 patients were enrolled and randomized. For patients who consent to voluntary MRI, their liver, internal organs and skin are examined. Lower body fat content is evaluated.

[0098] [Table 1]

[0099] Screening (Day 21 to Day 8) Participants will undergo an on-site screening visit to determine their eligibility for the trial. After screening, subjects whose eligibility for inclusion is confirmed will undergo baseline evaluation. It can be done.

[0100] Planned lifestyle interventions (U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research 2020 08) A 500kcal calorie deficit per day, and US sugar for optimal blood sugar control. The American Diabetes Association (ADA) Diet according to guidance, with a protein intake of at least 1.2 g / kg / day to support muscle anabolism, including diet counseling for weight loss. Patients receive counseling on physical activity and are encouraged to follow the guidelines of the US Department of Health and Human Services (2008) (see SOM). When eligibility is confirmed, these interventions are initiated at the time of screening. Baseline (Day -7 to Day -1) Before dosing (Day 1), patients eligible for inclusion after screening return to the clinic for baseline evaluation. To facilitate the conduct of the clinical trial, patients may choose to reside on Day -1 to complete the baseline evaluation before dosing on Day 1. Randomization and dosing (Day 1) Based on screening and baseline evaluation, eligible patients are randomized at a 1:1 ratio to receive either bemagrumab or placebo. Randomization: Patients are stratified into the following two strata according to baseline BMI.

[0101] [[ID=...]] ● BMI is 28 kg / m ~33 kg / m (including endpoints), and ● BMI exceeds 33 kg / m and is 40 kg / m or less (including endpoints).

[0102] The administration of bemagrumab or placebo is performed by intravenous infusion over 30 minutes, followed by an observation period including safety, tolerability, and PK sampling. After all evaluations, patients may be discharged from the facility of the responsible investigator if the responsible investigator determines that the patient is medically stable and in good general health and no further observation is required.

[0103] 2 2 2 2 Please note that in the original text, there are some tags like etc. which seem to be some kind of internal identifiers or specific formatting elements in a particular system. They are just preserved as they are in the translation without any change in their semantics for the purpose of this translation task. Also, the text seems to be a bit fragmented in terms of the numbering and structure, but I've tried to make sense of it and translate it as accurately as possible following the given rules. If there are any specific clarifications needed regarding the original text, it would be helpful for a more polished translation.​​​​​​​​​​​​ 。

[0104] Treatment period (Day 1 - Day 336) Throughout the trial, patients continue background monotherapy in accordance with eligibility criteria (see selection criteria). All participants can continue to receive diabetes treatment and can undergo background therapy eligibility screening. Throughout the trial, patients continue background monotherapy in accordance with eligibility criteria (see selection criteria). All participants can continue to receive diabetes treatment and can undergo background therapy eligibility screening. 。

[0105] Administration of bemaglumab or placebo is performed over a total of 12 administrations, once every 4 weeks, by intravenous infusion over 30 minutes followed by an observation period of 1 hour. Bemaglumab is administered at 10 mg / kg based on body weight, with a dose ceiling of 1200 mg for body weights over 120 kg. Placebo is provided as D5W, a 5% dextrose solution. Administration of bemaglumab or placebo is performed over a total of 12 administrations, once every 4 weeks, by intravenous infusion over 30 minutes followed by an observation period of 1 hour. Bemaglumab is administered at 10 mg / kg based on body weight, with a dose ceiling of 1200 mg for body weights over 120 kg. Placebo is provided as D5W, a 5% dextrose solution. Administration of bemaglumab or placebo is performed over a total of 12 administrations, once every 4 weeks, by intravenous infusion over 30 minutes followed by an observation period of 1 hour. Bemaglumab is administered at 10 mg / kg based on body weight, with a dose ceiling of 1200 mg for body weights over 120 kg. Placebo is provided as D5W, a 5% dextrose solution. Administration of bemaglumab or placebo is performed over a total of 12 administrations, once every 4 weeks, by intravenous infusion over 30 minutes followed by an observation period of 1 hour. Bemaglumab is administered at 10 mg / kg based on body weight, with a dose ceiling of 1200 mg for body weights over 120 kg. Placebo is provided as D5W, a 5% dextrose solution. 。

[0106] Throughout the trial, patients receive regular monitoring and advice on diet and physical activity as part of their monthly facility visits. Throughout the trial, patients receive regular monitoring and advice on diet and physical activity as part of their monthly facility visits.

[0107] During the treatment period, patients are required to return to the facility of the trial responsible physician for medication approximately every 4 weeks. During these visits, patients are evaluated for safety, tolerability, PK, and efficacy. During the treatment period, patients are required to return to the facility of the trial responsible physician for medication approximately every 4 weeks. During these visits, patients are evaluated for safety, tolerability, PK, and efficacy. 。

[0108] The treatment period ends 4 weeks after the last administration (Day 308 / Week 44).

[0109] Follow - up (Day 364 - Day 392) After completion of the treatment period, patients have an 8 - week follow - up period with regular monitoring of safety and efficacy until the end of the trial visit (EOS) conducted 12 weeks after the last administration of the investigational drug (Week 52). After completion of the treatment period, patients have an 8 - week follow - up period with regular monitoring of safety and efficacy until the end of the trial visit (EOS) conducted 12 weeks after the last administration of the investigational drug (Week 52). 。

[0110] Rationale for setting the clinical trial design The rationale for setting the main elements of the clinical trial design includes the following: ● Randomization: Reduces the possibility of imbalance in subject characteristics (e.g., age, BMI) between treatment groups. Therefore. ●Stratification: BMI is used for parameters of body composition / weight and HbA1c (internal data). It was selected as a stratification parameter because it is an important predictor of the response. This patient population The expected median BMI in this region is 33 kg / m². 2 (Internal data), and therefore central The two layers above and below the value (including the endpoints) represent the balance between placebo and activity in each layer. This ensures a balanced presentation, that is, layers of roughly the same size between the two groups. ● Blinding of subjects and principal investigators: Treatment allocation, reporting of adverse events, and causal relationships To reduce the risk of bias in evaluation. Furthermore, this design allows for the assignment of treatments. Potential interactions of intentional or unintentional behavioral changes made by known entities. Reduces the entanglement effect. ● Placebo group: Including a placebo provides a comparison group with bimaglumab and allows for a double-blind study. Included to enable the design. ●Lifestyle interventions: In clinical trials using anti-obesity drugs, lifestyle interventions were used as a backup for primary treatment. For the ground, the therapeutic benefits in terms of weight / composition need to be demonstrated. 500kc A daily calorie deficit in AL is a standard approach and induces weight loss over the treatment period. It is predicted that this will occur. This will also enhance the effects of bimaglumab on body composition and weight. The American Diabetes Association (ADA) walking program was obtained by the population in this clinical trial. It is adjusted to suit different types and provides a gentle and easy approach for physical activity. It is known that exercise enhances the effect of bimagrumab on muscle function, which may support the therapeutic benefit of bimagrumab on body composition and body weight. ● Appropriate protein intake: This is important for optimal muscle maintenance / growth, and a protein content of 1.2 g / kg / day is recommended to compensate for calorie deficiency.

[0111] Standard treatment for diabetes: Patients should continue the standard treatment for diabetes, which allows for the evaluation of the additional therapeutic benefit provided by bimagrumab in terms of blood glucose parameters. Oral monotherapy for diabetes is suitable for patients in the early stages of the disease state and thus without significant co-morbidities. Monotherapy is restricted to metformin or DPP4 inhibitors, as these drugs are less likely to affect body weight and thus confound the trial results.

[0112] Rationale for setting dose / regimen, route of administration and treatment duration Rationale for dose setting In healthy volunteers (HV) and sIBM patients, a dose of 10 mg / kg of bimagrumab showed anabolic effects, with exposure levels (i.e., above 10 μg / mL) provided at dosing intervals of 4 weeks [CBYM338X2102 (N = 6 subjects), CBYM338X2104 (N = 47 subjects)] for up to 6 doses [CBYM338X2109 (N = 35 subjects)] and maintained for up to 1 year [CBYM338B22 03 (N = 54 sIBM patients)]. The threshold for the minimum target exposure of bimagrumab is approximately 10 μg / mL, and non-linear clearance is observed at concentrations below this, suggesting loss of complete receptor saturation and loss of target-mediated pharmacokinetics. In clinical trials to date, in HV ​​​​​​​​​​​ In both cases, bimaglumab concentrations of approximately 10 μg / mL or higher were observed for 4 weeks, and in sIBM patients for more than 1 year. It is safe, well-tolerated, and shows an increase in thigh muscle mass. The 6-week toxicity study compared human exposure at a steady state of 10 mg / kg with AU For C and Cmax, the NOAEL (300 mg / kg / week) is approximately 300. It showed chronic exposure levels of 2x and 55x.

[0113] In this clinical trial, the dosage was weight-based for patients weighing up to 120 kg. For patients weighing 120kg to 140kg, the maximum dose is 1200mg. It has been proven to reduce the variability of exposure in subjects / patients, and as needed This will be carried out. The magnitude of the impact on the pharmacokinetics, exposure, and safety profile of bimaglumab. Because the effects of body weight and body composition (body fat mass %) relative to lean body mass %) are uncertain, the upper limit The dosage is selected based on body weight exceeding 120 kg. To date, pharmacokinetic data have been obtained for obese individuals. The study was limited to elephants, and included overweight to obese subjects (N=10) with insulin resistance. In a clinical trial conducted with bimaglumab in obese healthy subjects (N=6), the dose-response ratio was The largest elephant recorded weighed 116 kg. The maximum dose of bimaglumab administered to date is 116 kg. Intravenous administration, 3500 mg (30 mg / kg) as a single dose for a maximum body weight of 116 kg. The dose was [amount]. This dose did not indicate excessive exposure, and no safety issues arose. These subjects The upper limit for this drug is to avoid excessive exposure and to ensure safe anabolic effects over a 4-week dosing interval. To maintain the bimaglumab level near the threshold, it is selected. Specifically, The amount of 1200 mg corresponds to 10-8.6 mg / kg for a body weight range of 120-140 kg. The dosage is converted based on body weight in the range of kg, which, for bimaglumab, minimizes overdose. The risk of excess exposure is expected to result in exposure levels within a safe and effective range.

[0114] Basis for setting the treatment period The 48-week treatment period allows for the temporal profile of bimaglumab relative to body fat mass and the most... It is chosen to capture a large effect. The ceiling effect is typically achieved by bimaglumab-induced fat loss. While an increase in volume is observed, the loss of body fat mass continues for 24 weeks, and even up to 64 weeks. Even over this period, it does not appear to reach a plateau (internal data).

[0115] Basis for setting the follow-up period The 8-week long-term follow-up period involved off-control of body fat mass, lean body mass, and blood glucose. Selected to monitor the duration of the therapeutic effect of bimaglumab on the treatment. Last dose The EOS visit, which takes place 12 weeks later, is part of the drug-free period for bimaglumab exposure related to anabolic effects. It covers the period (approximately 8 weeks).

[0116] Rationale for selecting comparator drugs Based on the following rationale, a placebo will be used as the comparator drug in this study. ●A placebo-controlled drug is necessary to maintain a double-blind design. ●Since the change from baseline in the bimaglumab treatment group is the primary determination of efficacy, The placebo group was not intended as a first-line efficacy comparator to bimaglumab.

[0117] Rationale for selecting background therapy This is an anti-obesity clinical trial in patients with T2D, and the primary objective is to assess body composition. This is the effect of bimaglumab. The improvement in blood glucose control occurs as a result of the improvement in body composition. It is possible, but in order to avoid worsening blood sugar control, patients still have their background It is necessary to consistently maintain T2D therapy. T2D treatment is necessary for the homogeneity of the clinical trial population. Limited to monotherapy to ensure data interpretability. Monotherapy includes metformin, The treatment is limited to a class of drugs with minimal impact on body weight, including DPP4 inhibitors. If improvement in blood glucose control is observed during the clinical trial, an antidiabetic drug will be administered to prevent hypoglycemia. A decrease in placement is observed.

[0118] treatment Investigational treatment and control drug The LIVI (liquid in the vial) of the investigational drug, BYM338 (bimaglumab) 150 mg, is Prepared by Novartis and supplied to the principal investigator's facility as an open-label bulk drug. It will be administered. The preparation of the investigational drug is detailed in a separate pharmacy manual. Placebo will be administered depending on the facility. This is an injection solution of 5% dextrose (D5W) in water that is supplied.

[0119] [Table 2]

[0120] The investigational drug will be received by a designated person at the clinical trial site, handled safely and appropriately, stored, and managed by the clinical trial manager. It must be stored in a secure location accessible only to the assigned physician and designated staff. Upon receipt, the investigational drug should be stored according to the instructions clearly stated on the drug label. The tube status must be properly monitored, and appropriate temperature logs must be maintained as source data. Appropriate documentation regarding patient-specific dispensing processes must be maintained. Bulk drug labels The instructions are in the local language, comply with the legal requirements of each country, and cover drug storage conditions. It includes information about the patient, but does not include patient information.

[0121] Further clinical trial procedures This clinical trial does not involve any further treatments other than the investigational drug and the control drug.

[0122] Background therapy Metformin or DPP4 inhibitors are used as background for patients to be eligible for clinical trials. It is required as a therapeutic treatment.

[0123] Treatment group Patients will be assigned in a 1:1 ratio to one of the following two treatment groups: Clinical trial procedures are defined as follows: ●BYM338 (bimaglumab) 10 mg / kg, maximum 1200 mg / month (12 doses) ● Monthly placebo (12 doses)

[0124] Efficacy / Pharmacodynamics Pharmacodynamic evaluations are specified below, and are the evaluations specified in the Facility Management Manual (SOM). This includes methods for recording the data. Evaluations are performed and samples are collected at defined points in time.

[0125] MRI and DXA images are centrally read by the CRO (Contract Research Organization).

[0126] Pharmacodynamic (PD) samples are obtained and evaluated for all patients.

[0127] 1. Blood glucose control assessment Fasting insulin and blood glucose levels Fasting blood glucose and insulin are taken at different times.

[0128] HbA1c HbA1c reflects the average glucose concentration over the past three months, and therefore, This provides a useful indicator of bimaglumab's glycemic control over that period. This is a standard endpoint used to evaluate the glycemic effect of certain antidiabetic drugs. HbA1c is a key blood glucose parameter that correlates with a reduced risk of diabetic complications.

[0129] HOMA-IR Patients undergo the Homeostasis Assessment Model for Insulin Resistance (HOMA-IR) and HOMA-I To estimate the degree of insulin resistance using the reciprocal of R, fasting at the time of screening Get tested for insulin and blood sugar levels.

[0130] QUICKI QUICKI is for people with diabetes and elevated fasting blood glucose levels, for example, above 170 mg / dl. In patients, it is considered a better estimate of insulin resistance than HOMA-IR. It is valued (Yokoyama et al 2004). QUICKI is fasting blood glucose HOMA-IR is a derived value of the insulin sensitivity index using insulin levels. This provides further supplementary information to what was obtained (Hrebicek et al 200 2).

[0131] 2. Imaging DXA scan Dual-energy X-ray absorptiometry (DXA) measures total fat and lean body mass (FBM and Body composition, including LBM (Left-Limb Fat) and limb skeletal fat and muscle mass (aFBM and aLBM). It is used to evaluate the changes. The DXA instrument generates and splits into two energies. Using an X-ray source, bone mineral content and soft tissue are measured, and fat and lean body mass are determined from them. Body weight (fat-free mass) (or lean body mass) s)) is estimated. The test is rapid (approximately 5-6 minutes), accurate (0.5-1%), and non-invasive. Therefore, DXA scanners require only 5% accuracy to detect changes in muscle mass. ru.

[0132] Quality assurance is a critical issue in the use of DXA scans to determine body composition. The manufacturer and model of the DXA device should be consistent, and their calibration should be performed through clinical trials. It should be monitored using a standardized scan acquisition protocol and appropriate and immutable The use of scan acquisition and analysis software is essential to achieving consistent results. Similarly, because there is variability in the interpretation of scans, centralized scanning by experienced staff is necessary. It is important to utilize 2D analysis.

[0133] Data collection and processing are handled by imaging CROs supporting clinical trials. This is explained in the Zing Code.

[0134] MRI scan Magnetic resonance imaging (MRI) is used to determine the percentage of fat in the liver (% fat percentage or %FF). , visceral and subcutaneous adipose tissue volume in the abdominal region, as well as paraspinal muscle cross-sectional area and associated fat Evaluate the changes in content (both intermuscular adipose tissue -IMAT and muscle FF content). The images are optimized for water / fat separation and are compatible with the MRI system's capabilities. By using a measuring pulse sequence, the data is acquired in the axial plane.

[0135] 3.Physical measurements ● Height ● Weight ● Waist circumference ●Temple enclosure ●Ratio of waist circumference to hindquarter circumference ● Body Mass Index (BMI) is calculated (weight (kg) / [height (m)] 2 )

[0136] 4. Measurement of physical function performance Exercise program The ADA Walking Guidelines are recommended. See SOM for further details. I want to be treated that way.

[0137] Timed Chair Stand The timed chair stand test is a short physical performance test. Similar to the components of the ance battery (Patel et al 2014) This refers to the ability of a person to stand up from a chair once, and then multiple times in succession, without using their arms. This is an evaluation. This test does not require advanced skills and can be performed in a clinic or similar setting. It can be carried out within the space of the device. The SOM includes a list of equipment, settings, and instructions. A description of the chair stand test, including the following, is available.

[0138] Handgrip strength test The purpose of this test is to measure the maximum isometric strength of the muscles in the hand and forearm. As a general rule, people with strong hands tend to have strong hands in other areas as well, so this test is often effective in determining strength. It is used as a general test.

[0139] 5. Patient-reported outcomes PRO: The impact of weight on quality of life - Lite The effect of body weight on Quality of Life-Lite (IWQOL-Lite) is To quantitatively assess individuals' perceptions of how their weight affects their daily lives. This is a research method used for weight loss. This method uses indicators that go beyond the realm of physical measurements of weight loss. Therefore, it is particularly useful for verifying the effectiveness of treatments for obesity.

[0140] DTSQ (Diabetes Treatment Satisfaction Questionnaire) The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was first developed in the early 1980s. Currently, it is widely used, especially in clinical trials, but it is also used for routine clinical surveillance. This is available in over 100 languages. The original DTSQ now has a potential ceiling effect. (That is, respondents rate their highest or near-highest satisfaction at baseline, and follow-up Developed to overcome situations where the top may show little or no improvement. To distinguish it from the DTSQ modified version (DTSQc), the status version (D It is referred to as TSQs.

[0141] Analysis of linear variables The primary objective of this clinical trial was to measure bima in relation to body fat mass at weeks 24 and 48 of the treatment period. The objective is to evaluate the effects of glumab.

[0142] variable The primary efficacy variable was the change in body fat mass from baseline at weeks 24 and 48. ru.

[0143] Statistical models, hypotheses, and analytical methods The design of this clinical trial is based on 1) statistical significance in fat mass (superior treatment effect, 10% unilateral reduction). Bell); and 2) Clinical relevance of changes in body fat mass (estimated median treatment effect of ≥5%), This allows for evaluation of effectiveness based on a dual criterion. A 5% weight loss is considered an overweight condition with T2D. It has been shown to lead to clinical benefits in the severe / obese population (Franz et al. (1 2015). Body fat loss equivalent to weight loss is associated with glycemic control in similar populations. Similar clinical benefits are expected, such as those in the field of [specific area].

[0144] Randomization is used to achieve an approximate balance of BMI distributions across the two treatment groups. In addition, BMI categories (28 kg / m2 to 33 kg / m2, over 33 kg / m2) The population is stratified by the threshold of 40 kg / m2 or less. The cutoff value of 33 kg / m2 is used for that population. This represents the predicted median BMI (based on internal data), and therefore, two random The fossilized layers are expected to have similar sizes. However, layers of the same size are forced It is not done. To ensure the precise accuracy of the treatment effect in both layers, a minimum of 1 Zero patients are targeted for inclusion into a smaller group.

[0145] A longitudinal model was used to explain body fat mass over time (time was modeled as a continuous variable). (and) using all data collected from both randomization strata, baseline body fat mass The treatment group and baseline BMI were adjusted using random intercepts and random gradients. The changes in body fat mass at weeks 4 and 48 are estimated from the model. As a supporting analysis... The percentage of patients who achieved at least 5% fat loss by week 24 and week 48 was compared between the treatment group and the treatment group. That's what I'll present.

[0146] Handling / terminating / canceling missing values The above main analytical models are valid under the assumption that data is randomly missing. If the dropout rate exceeds 10% in any group, the missing data will be processed. Therefore, other analytical methods are used to evaluate the sensitivity of the results to different methods.

[0147] Sensitivity analysis To assess the sensitivity of conclusions regarding primary effectiveness for missing data, the dropout rate is predicted. If the measurement is higher, other models (such as pattern mixing models) can be used.

[0148] Analysis of quadratic variables A particularly interesting secondary efficacy variable was the change in HbA1c at weeks 24 and 48. be.

[0149] Blood glucose control and insulin sensitivity (fasting blood glucose and insulin, HOMA- IR (QUICKI) and anthropometric measurements (weight, BMI, waist circumference, waist circumference to hip circumference ratio) And other parameters such as lean body mass (LBM) measured by DXA are other secondary effective It is a sex variable.

[0150] Efficacy / Pharmacodynamics The secondary variable of HbA1c was analyzed in the same way as body fat mass, and the relationship between HbA1c and Vimag Statistical significance of lumab therapy (superior treatment effect, unilateral 10% level); and clinical aspects of this effect The relationship (median treatment effect at 0.5%) is evaluated. A certain model is used to assess HbA1c This explains the changes in HbA1c over time, including the changes at all target points in time (including week 48). The model is used for estimation. The analysis is performed after background antidiabetic drug or dose change. The observed data was cut off. This analysis was observed when background drug / dose adjustments were made. Because it is based on the data (HbA1c, FPG), it is predicted to be unbiased. This increases the likelihood of randomly missing (MAR) censorship data after medication changes. Other adjustments regarding background antidiabetic medications may be considered in the model. As a supporting analysis of the changes in response, an overview of the increase (and decrease) in background antidiabetic medications is provided. Possible. Background changes in antidiabetic drugs include changes in the daily dose and / or a second It is defined as an addition of medication.

[0151] definition The term "obesity" is based on BMI in both young people and adults, but the definition is not directly compared. No. Among adults, there are cutoff points set based on health risks, on the other hand. In children, the definition is statistical and based on comparison with a reference population. BMI is a kilogram. Divide the weight in lambs by the square of the height in meters, and round to one decimal place. Obesity in adults is defined as 30 kg / m². 2 The above is defined as BMI.

[0152] Obesity among young people accounts for 95 percent of age- and sex-specific percentages of the CDC growth charts in 2000. It is defined as a BMI above the average.

[0153] The term "overweight" refers to a condition where 25 kg / m² is used. 2 More than 30kg / m 2 Based on a BMI of less than Ku.

[0154] Being overweight can also be a fatal condition (such as diabetes, hypertension, or a family history of early-onset coronary artery disease). It may be associated with at least one additional risk factor for (stroke, MI, heart failure, or sudden death).

[0155] Furthermore, the overweight conditions described herein are those associated with diabetes, hypertension, and premature coronary artery disease. At least one further risk of fatal illness (stroke, MI, heart failure, sudden death) (including medical history) It may be associated with risk factors.

[0156] Different subjects may have the same BMI, but their fat-to-muscle ratios may differ, therefore, BMI This is not always a good indicator for classifying overweight and obesity. In other words, even if the percentage of body fat is low, the BMI can still be high, and in this case, the subject is... Based on BMI classification, one may be mistakenly identified as overweight or obese. In addition to BMI, other indicators Standards, namely waist circumference and body type index -ABSI-, were used (Bouchi et al.). (2015), DXA and MRI imaging of muscle, fat, and fat distribution It is often used in clinical trials to quantify proportions.

[0157] In this specification, the term "body composition" refers to the proportion of fat and muscle in the human body. It is used to clarify. Muscle tissue occupies a smaller space in our body than adipose tissue. Therefore, our body composition, like our weight, determines whether we are lean or not.

[0158] Two people of the same sex and weight may appear completely different to each other because their body composition is different. There is a possibility that it will happen.

[0159] "Lean body mass" is a component of body composition calculated by subtracting body fat mass from total body weight. Weight is the sum of lean body mass and fat.

[0160] The formula is as follows: LBM = BW - BF Lean body mass = body weight - body fat LBM + BF = BW Lean body mass + body fat = body weight

[0161] The percentage of lean body mass is not usually cited (it is typically considered to be 60-90%). (It can be calculated). Instead, the complement, which is body fat percentage, is calculated, and is typically between 10% and 40%. Lean body mass (LBM) is important because body fat is not very related to metabolism, so the appropriate level of medication It is said to be a better indicator than total body weight for prescribing medications and for evaluating metabolic disorders. It has been revealed.

[0162] The term "body fat mass" refers to the part of the human body that is strictly composed of fat. Measurement should be performed using heavy energy absorption spectrophotometric analysis (DXA), MRI, or bioelectrical impedance analysis. It is possible.

[0163] The term "central fat storage" refers to the following:

[0164] Obesity is defined as a condition of abnormal or excessive fat accumulation in adipose tissue. The amount of excess fat in a given value, and the local distribution of different stored fats, both cast a shadow on the health of obesity. It plays an important role in determining the sound. Obesity is classified as central / android obesity, It can be classified into peripheral / gynoid obesity and android obesity, which is more common in men. Typical and more characteristic of gynoid obesity, it is more common in women.

[0165] Not all obesity is associated with a harmful metabolic profile and increased cardiovascular risk. There is considerable evidence to support the argument that this is not the case. In fact, body fat distribution (i.e., peripheral body fat) The relative presence of abdominal fat to body fat is more important than the degree of obesity itself in terms of metabolic and cardiovascular risk. It was considered a better indicator. In men who tend to accumulate fat in the trunk area, BM While an increase in BMI is associated with an increased risk of cardiovascular disease, in women, BMI is generally associated with an increased risk of cardiovascular disease. It is a poor indicator / substitute for K.

[0166] Trunk fat mass is subdivided into subcutaneous (SC) fat (in the abdominal wall) and visceral adipose tissue (in the abdominal cavity). It is possible. Subcutaneous fat and visceral fat are distinguished by their anatomical structure, cellular composition, and endocrine structure. They differ significantly in terms of function and cellular regulation. Compared to SC, VAT is more cellular, vascular, It is neuroinnervated, infiltrates inflammatory and immune cells, and is associated with insulin resistance, type 2. Higher risk factors for diabetes and cardiovascular disease, both directly and indirectly. This leads to increased metabolic activity and the release of pro-inflammatory cytokines. In contrast, subcutaneous fat mass In particular, stored fat in the thighs and buttocks is insulin-sensitized, anti-inflammatory, and anti-atheroma-causing. It was associated with the constitutive secretion of adiponectin, which provides a vital effect. Mild inflammation was associated with muscle wasting and This is related, and in turn, it further worsens insulin sensitivity, leading to the development of type 2 diabetes. This could increase relative risk.

[0167] Therefore, even without obvious obesity (i.e., BMI less than 30 kg / m2), An imbalance between central and peripheral fat storage (central fat accumulation) is associated with significant insulin resistance. Related to systemic mild inflammation that collectively promotes resistance, metabolic changes, and accelerated atheroma formation. They can be linked.

[0168] In clinical practice, to estimate abdominal obesity, body measurements such as the ratio of waist circumference to hip circumference are used. Although these measurements are widely used, these anthropometric measurements do not distinguish between visceral and subcutaneous fat in the abdomen. It cannot be distinguished and is associated with inaccuracies. Computed tomography (CT) or dual energy - More advanced techniques such as X-ray absorptiometry (DXA) allow for a more direct assessment of body fat mass / Measurements can be provided. CT is advantageous for distinguishing between VAT and SAT. DXA evaluates the distribution of body fat mass between predefined anatomical regions (arms, legs, trunk). This is valuable and helps distinguish between gynoid android fat accumulation.

[0169] The term "Type II diabetes," also known as "Type 2 diabetes," was previously referred to as "non-insulin-dependent diabetes." It is called "diabetes disease" or "adult-onset diabetes," and accounts for 90-95% of all diabetes cases. This includes individuals with phosphorus resistance who typically have (not absolute) relative insulin deficiency. At least initially, and often throughout their lives, these individuals need to survive. It may not be necessary to treat it with insulin. There are various causes of type 2 diabetes.

[0170] Although the specific etiology is unknown, autoimmune destruction of B cells does not occur, and the patient is not known to others. They do not have any of the causes of diabetes. Most, though not all, people with type 2 diabetes have excessive Being overweight or obese. Excess weight itself causes some degree of insulin resistance. Patients who are not obese or overweight according to conventional weight standards have a percentage of body fat distributed mainly in the abdomen. The risk is high. Hyperglycemia develops gradually, and in the early stages, patients often have classic diabetes. Because the symptoms are not severe enough to be noticed, type 2 diabetes often goes undiagnosed for many years. This often happens. Nevertheless, even in undiagnosed patients, macrovascular and microvascular complications can occur. There is a high risk of developing vascular complications.

[0171] The term "comorbidity of obesity or overweight": Obesity is associated with type 2 diabetes or glucose intolerance. Sex, prediabetes, high triglycerides, physical disability, osteoporosis, kidney disease, obstructive sleep apnea, Endocrine and reproductive disorders such as sex hormone disorders, polycystic ovary syndrome, or male hypogonadism, Osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, and stroke, Serious conditions including, but not limited to, gallstones, high blood pressure, and changes in the sex hormone profile. It is related to chronic disorders.

[0172] "Glucose intolerance" is defined as the inability to properly metabolize glucose.

[0173] "Insulin sensitivity" refers to how sensitive the body is to the effects of insulin. People who are said to be insulin-sensitive tend to have lower blood sugar levels than those with low insulin sensitivity. A smaller amount of insulin is needed to achieve this. Insulin sensitivity varies from person to person, so consult a doctor. Tests are performed to determine how sensitive an individual is to insulin. can.

[0174] "Insulin resistance" reduces the effectiveness of the hormone and hinders glucose uptake in muscle tissue. This causes a decrease in glucose absorption, which impairs glucose oxidation and glycogen synthesis. Furthermore, insulin resistance results in insufficient suppression of hepatic glucose production in the liver. It is defined as the state of obesity, which is caused by increased lipolytic activity in the plasma. Increased visceral fat mass accompanied by elevated free fatty acids (FFA) impairs insulin action. It worsens insulin resistance (Reaven et al., 1988), and this is due to fat. This is a known mechanism of toxicity (DeFronzo, 2004).

[0175] In this specification, "improvement of insulin sensitivity" and "treatment of insulin resistance / low The term "below" shall be interpreted as referring to equals.

[0176] High concentrations of FFA in skeletal muscle cells trigger insulin via the Glut4 transporter. This results in a decrease in intracellular glucose transport induced by stimuli (Dresner et al.). (1999), in hepatocytes, the rate of gluconeogenesis and glucose release from the liver is increased. and increased insulin secretion from β cells in response to transient increases in FFA or chronic hyper It produces inhibitory effects depending on the level (Boden, 1997). Insulin resistance and As a result of lipotoxicity, glucose uptake from fat and muscle cells, as well as in the liver, More insulin is needed to induce glycogen synthesis (Ce Falu et al., 2016). Excessive insulin production by pancreatic β-cells is This is a physiological response to phosphorus resistance, leading to decreased β-cell function and ultimately prediabetes. and can lead to type 2 diabetes (Donath et al., 2005). The term "improvement of phosphorus sensitivity" refers to systemic responsiveness to glucose, which is as follows: It can be measured by [method]. 1. Insulin sensitivity index - inhibits glucose release from the liver and peripheral glucose consumption. By stimulating the endogenous insulin's ability to lower glucose in extracellular fluid, Measure. 2. Glucose clearance - glucose, calculated by dividing by the plasma glucose concentration per unit of body surface area. To measure the effect of changes in insulin concentration on glucose uptake rate, glucose crystals The pump method.

[0177] "Prediabetes" is characterized by abnormally high blood sugar levels (e.g., 100-125 mg / dL) and diabetes mellitus (diabetes vera). This is the pre-disease stage.

[0178] Fasting blood glucose impairment and impaired glucose tolerance are similar in their clinical definitions (blood glucose levels are the situation) These are two aspects of prediabetes (which are too high relative to the risk of diabetes), but physiologically they are distinct. Streptococcal resistance, metabolic syndrome (or syndrome X), and prediabetes. These are closely related to each other and have overlapping aspects.

[0179] "Antidiabetic treatment" for type 2 diabetes includes the following: ● Metformin. Generally, metformin is the first medication prescribed for type 2 diabetes. This is because the body's tissue sensitivity to insulin allows the body to use insulin more effectively. It works by improving sexual function. Metformin also reduces glucose production in the liver. It lowers blood sugar. Metformin may not be able to lower blood sugar levels sufficiently on its own. ru. ● DPP-4 inhibitors. These drugs also lower blood sugar levels. They can cause weight gain. No. Examples of these drugs include sitagliptin, saxagliptin, and vildagliptin. It is called linagliptin. ● Sulfonylurea. These drugs help the body secrete more insulin. Examples of drugs in this class include glybride, glipizide, and glimepiride. Possible side effects include hypoglycemia and weight gain. ● Thiazolidinedione. Similar to metformin, these drugs convert body tissues into insulin. In contrast, it is more sensitive. This class of drugs is used for weight gain, as well as heart failure and fractures. It is associated with other more serious side effects, such as an increased risk. These medications are generally not the first-line treatment. Pioglitazone is an example of a thiazolidinedione. ● GLP-1 receptor agonists. These drugs slow down digestion and help lower blood sugar levels. Their use is often associated with some weight loss. This class of drugs is Not recommended for use on the body. Exenatide and liraglutide are examples of GLP-1 receptor agonists. ●SGLT2 inhibitors. These are the newest diabetes medications on the market. They are drugs that the kidneys use to stimulate blood circulation. It works by preventing the reabsorption of sugar. Instead, the sugar is excreted in the urine. Examples include canagliflozin and dapagliflozin. ● Insulin therapy. Some people with type 2 diabetes also require insulin therapy. In the past, insulin therapy was used as a last resort, but today, due to its benefits... It is often prescribed earlier.

[0180] Normal digestion interferes with insulin ingested orally, therefore insulin must be injected. It is necessary. If necessary, an insulin-type mixture may be used day and night. In many cases, patients with type 2 diabetes receive insulin once a night with a long-acting injection. Start using n.

[0181] Insulin injections use a microneedle and syringe or insulin pen injector (cartridge). The use of a device that looks similar to an ink pen except that it is filled with insulin. include.

[0182] There are many types of insulin, each acting in a different way. For example, Slingullysine, insulin lispro, insulin aspart, insulin glargine Insulin detemir and insulin isophane are examples. [Examples]

[0183] The present invention will be described in more detail and specifically below with reference to examples, but this is the present invention It is not intended to limit the scope.

[0184] Example 1: Bimaglumab improves body composition and insulin sensitivity in patients with insulin resistance. do Clinical trial design. Clinical trial CBYM338X2206 ran from August 21, 2012 to 2014. Until October 25th, Clinical Re An exploratory Phase Ib, randomized, double-blind, placebo-based trial conducted by search, Inc. This was a controlled, single-center, single-dose study. It involved 16 healthy volunteers with insulin resistance. Participants were randomly assigned in a 10:6 ratio to receive bimaglumab 30mg over approximately 2 hours. A single intravenous infusion of g / kg or placebo was administered, followed by a 4-hour observation period. A 24-week follow-up was conducted after this single-dose treatment period. All subjects were in the study. Maintain your current (screening) level of physical activity and motor behavior throughout the period. The instructions were to proceed as follows: The primary endpoints were systemic insulin sensitivity and body composition. The objective was to determine the effect of bimaglumab. Patients were assessed at baseline and after drug treatment. The evaluation was performed at week 10 (day 71), followed by a 24-week follow-up. This clinical trial was conducted as follows: ICH Harmonized Tripartite Guidelines for Good Clinical Practice, applicable local regulations, and Designed in accordance with the ethical principles set forth in the Lucinki Declaration. Clinical trial protocol and all The modifications are for the facility in Sunrise, Florida, 33323, USA, which is an independent facility. It was reviewed by the Institutional Review Board (IRB).

[0185] Target population: Adult men and women aged 18-65 who provided informed consent. Elephants were included in the clinical trial. Other selection criteria included a body mass index (BMI) of 18-45 kg / m². 2 , oyo Blood glucose levels 140-199 mg / dl 2 hours after administration of 75g oral glucose (OGTT) Alternatively, it can be defined by homeostasis model assessment - insulin resistance (HOMA-IR) of 2.6 or higher. The diagnosis was glucose intolerance. The calculation is as follows: HOMA-IR=empty Abdominal blood glucose (mg / dL) × Fasting insulin (mU / L) / 405. The main exclusion criteria are: All diseases, especially diabetes, testosterone, growth hormone, systemic glucocorticoid therapy She was a patient under the law and a woman of childbearing potential.

[0186] Hyperinsulinic euglycemic clamp method. (Le et al, 2009) Standardized dinner Following the intake of (10kcal / kg; 50% carbohydrates, 30% fat, 20% protein) After fasting for at least 12 hours overnight, the subjects were given Biostator (Indiana, USA). It was connected to Elkhart (Life Science Instruments). I placed one hand under the heating pad to allow for the collection of arterial and venous blood. To maintain blood glucose levels at the target level of 90 mg / dL, insulin should be 1 mU / kg-1 Intravenous infusion was administered at a rate of 0.min-1 for 180 minutes (Step 1). After 180 minutes, another 1 Increase the insulin infusion rate to 2.5 mU / kg-1 min-1 for 80 minutes (step 2) Steady-state hyperinsulinemia was sufficient to prevent hepatic glucose excretion. Insulin infusion was discontinued at the end of Phase 2. It was necessary to maintain blood glucose levels at 90 mg / dL. The required 20% v / v glucose infusion rate (glucose infusion rate, or GIR) (mg. (kg-1.min-1) throughout the euglycemic hyperinsulinic clamp period, especially during both periods. The last 30 minutes (in a quasi-steady state) were recorded (steps 1 and 2). GIR is the ins It was used to calculate the phosphorus sensitivity index (i.e., M, M1, S1). Insulin sensitivity measurement The steady-state period for determination is 150-180 minutes in steps 1 and 2. Defined. The total duration of the two-step HE clamp procedure was approximately 7 hours. Serum insulin Blood samples for measuring 0, 150, and 1 in step 1 are used to measure the glucose and glycation concentrations. After increasing to a higher insulin infusion rate in Step 2, at 60, 170, and 180 minutes. Samples were collected at 150, 160, 170, and 180 minutes.

[0187] IVGTT. After a minimum of 8 hours of overnight fasting, subjects were subjected to evaluation of phase I insulin release. I underwent an intravenous glucose tolerance test. My basal blood glucose levels were measured for glucose and insulin. Samples were taken at -5 minutes and 0 minutes. At 0 minutes, a glucose dose of 0.3 kg / kg body weight was taken. The bolus was administered as D50 (50% solution in sterile water). Bolus delivery was completed within 2 minutes. Blood samples were taken at 2, 4, 6, 8, 10, 15, and 20 minutes, and then the crab... The urea was removed.

[0188] PET FDG-18 / CT scan for BAT evaluation. Baseline and first In week 0, all subjects were subjected to "cold" exposure and "warm" (or thermally neutral) conditions. , radioactive 18 Positron emission tomography using fluorodeoxyglucose (FDG) PET was performed (Virtanen KA et al, 2009). Under cold exposure. BAT activation is performed in a room adjacent to the scanner room, with an ambient temperature set to 17-18°C. This was achieved over an hour by cooling the subject while wearing thin clothing. PET During the CT scan itself, the scanner room temperature is set to 17-18°C to maintain cold exposure. The scan obtained under warm conditions (temperature of 22-24°C) was compared to the scan obtained under cold conditions. The scans were performed the day before or the day after the procedure. All scans were obtained under overnight fasting conditions. Shoulder region Immediately after dynamic acquisition, the lower limbs were scanned to show the gastrocnemius muscle as an example of fast-twitch and slow-twitch muscle tissue. The soleus muscle was imaged. PMOD software was used to image each voxel and the aorta. PET images were quantified using time-activity curves and a 128×128×63 matrix. Imaging of body metabolic rate measurements at micromolar glucose / 100g / min within the body, The expected values ​​were 5-15. We compared PET scans obtained under "cold" and "warm" conditions. This allowed quantitative measurements to be extracted from each dataset.

[0189] DXA scan. (Albanese et al, 2003) All subjects were concentrated. Can analysis (Novartis CRO) showed baseline, week 6, week 10, and week 14. Whole-body dual-energy X-ray absorptiometry (DXA) scans completed in week 1 and week 24 I received it. All scans require the subject to lie face up on the DXA table, and the carrier A blunt phantom was used to ensure consistency of DXA readings. These skims From Chan, absolute values ​​and baseline values ​​of lean body mass (LBM) and fat body mass (FBM). The relative change from was calculated. The test took 1-2 minutes. The effective dose of the DXA whole-body scan was calculated. The reading was 2.1 μSv.

[0190] Statistical analysis. Data analysis was conducted under the direction of Novartis staff. High insulin We analyzed pharmacodynamic (PD) variables (M / I) evaluated from the normal glucose clamp method to determine the target. Endpoints are changes from baseline values, and these endpoints are analyzed separately. Before the analysis, a logarithmic transformation was applied to each endpoint. Logarithmic transformation relative to baseline. The converted ratios were used for treatments (bimaglumab and placebo) as fixed effects and covariates. The analysis was performed using the ANCOVA model with log baseline values ​​as the basis for treatment estimation. Values, contrast of treatment differences (bimaglumab-placebo), and corresponding inverse 90% confidence intervals. The corresponding 90% confidence intervals were used, along with the corresponding percent relative to baseline for treatment comparison. Placebo-adjusted percentages were provided for the baseline and raw values. Descriptive statistics of the percentage and absolute change from baseline of the PD variable are available at time and processing. Provided by group and step. AUC (Area Under Curve) and Cmax (Maximum Value) are The glucose and insulin profiles were derived using IVGTT. HbA 1c , fasting insulin and glucose for the same period, DXA parameters and body The heavy data were analyzed separately using a mixed-effects model for repeated measures. All values ​​were changes from baseline. DXA parameters and weight were logarithmically transformed. The ratio, as well as the change from baseline, were treated as fixed factors (bimaglumab and planar). (Sev), visit and visit × treatment interaction, log baseline / baseline as covariate. The analysis was performed using the ANCOVA model with the target as the random factor and the value of the treatment. Values, contrast of treatment differences (bimaglumab-placebo), and corresponding inverse 90% confidence intervals. The corresponding 90% confidence intervals were used, along with the corresponding percent relative to baseline for treatment comparison. Placebo-adjusted percentages were provided for both the target and baseline.

[0191] result The clinical trial population. The healthy volunteers enrolled in this trial were primarily Caucasian (94%). , male (81%), and overweight or obese (average BMI 29.3 kg / m²) 2 Range: 2 1.1–37.7, median 28.6 kg / m 2 ) was the case. All subjects had a score of 2.6 or higher. Insulin resistance as defined by HOMA-IR, not diabetes, and average Hb A 1c The rates were 5.49% (±0.39) in the bimaglumab group and 5% (±0.39) in the placebo group, respectively. The rate was 0.35% (±0.24). A total of 16 subjects were enrolled and were in the bimaglumab group. There were 10 people in the bimaglumab group and 6 in the placebo group. The average age was 42.2 years in the bimaglumab group compared to 6 in the placebo group. Except for the placebo group being slightly older at 47.3 years old, both groups had similar baseline characteristics. They were equivalent in this regard. All baseline laboratory findings were equivalent.

[0192] Changes in body composition. Measured by dual-energy X-ray absorptiometry (DXA) scanning. A significant treatment effect of bimaglumab was observed in body composition at week 10. Total lean body mass (LBM) increased with bimaglumab (mean 2.7% at week 10 [90 [% confidence interval (CI) 0.45, 5.01; p=0.049] (Figure 1A), the treatment effect was, It was observed as early as week 6 (the first scan after administration) and continued until the end of the trial (week 24). There was a tendency towards baseline. Furthermore, compared to placebo, the bimaglumab group Then, a significant decrease in total body fat (FBM) was observed in week 10 (mean -7.9%). [90% CI -12.5, -3; p=0.011]), this effect was already observed in week 6 (first Observed in post-administration scans, and persisted until the end of the trial (average -6.5% at week 24 [9]). 0%CI -11.2, -1.5; p=0.034) (Figure 1B). Interestingly, L The effect of bimaglumab on BM reached a plateau level after 6 weeks and was observed in FBM. Compared to a sustained decline, there was only an increase of about 1% between week 6 and week 14. Throughout the study, there was no significant impact on body weight in any group compared to baseline. In week 10, the absolute increase in LBM due to bimaglumab was 750g (±2) in the placebo group. The average loss was 2 kg (±1.4 kg) compared to 0.1 kg, and the absolute loss of FBM was bimaglu The average weight loss was 2.3 kg (±1.7 kg) with Mab and 470 g (±0.7 kg) with placebo. Ta.

[0193] Insulin sensitivity and HbA 1c Insulin sensitivity is two steps higher than normal insulin sensitivity. Measured by the glucose clamp method, and adjusted for serum insulin levels (I) It was reported as a ratio to phosphorus sensitivity (M). Compared to insulin sensitivity (M / I) at week 10. The efficacy of bimaglumab treatment was 21.8% per step [90% CI -8.9]. 62.7; p=0.250], 18.2% per step 2 [90% CI -7.4, [50.9; p=0.247] showed an increase. Insulin sensitivity also showed an increase in intravenous glucose. The effect was evaluated by a glucose tolerance test (IVGTT). The effect of bimaglumab treatment at week 10 was evaluated by glucose It showed a significant decrease in the insulin response to insulin loading, and there was no therapeutic effect on blood glucose levels. The area under the curve (AUC) for insulin decreased by 38% [90% CI -52.6, -1 9; p=0.008], the maximum insulin concentration (Cmax) decreased by 30.4% [90 [%CI -48.7, -5.6; p=0.056](Figure 2). In the bimaglumab group, placebo No difference in fasting plasma glucose was observed compared to the B group (p=0.674), while in the P group... In the sebum group, there was a significant decrease in glucose AUC compared to the bimaglumab group (10.3%, p= A value of 0.011 was observed. The hyperinsulinic euglycemic clamp method showed loss of body fat mass and insulin A linear and significant relationship was observed between increased phosphorus sensitivity and (p=0 for step 1). 041, p=0.028 for step 2), on the other hand, changes in lean body mass and insulin sensitivity No such correlation was observed with sex (p=0.982 for step 1). In step 2, p = 0.411) (Figure 3). HbA 1c Treatment effect of bimaglumab This was observed as early as week 6, showing a decrease of 0.22%, [90%CI -0.31, -0. 12; p < 0.001], this persisted until the end of follow-up at week 24 (mean -0.24%) [90%CI -0.33, -0.14; p<0.001] (Figure 4). In the racebo group, HbA1c levels were elevated around week 18. 1c It showed a slow deterioration (mean 0.11%) [CI [90% -0.01, 0.24; p=0.144], but not statistically significant.

[0194] Brown adipose tissue (BAT). The heat-generating capacity of BAT is at neutral ambient temperatures (i.e., "warm"). Measurements taken at 22-24°C and at the end of 90 minutes of cold exposure (i.e., "cold" 17-18°C). It is defined by the difference in the defined glucose metabolic rate (ΔGMR). Treatment with bimaglumab Before placement, this cold load caused the GMR to increase from 0.56±0.15 μmol / 100g / min The concentration increased to 0.67 ± 0.24 μmol / 100g / min (+19%, N=15, p=0). 12). At 10 weeks after drug administration, the placebo group showed a decreasing trend in fever response, and such Progression to further impairment of BAT activity was not observed in the bimaglumab group (ΔGMR). [Cold-Warm] Placebo: 0.23±0.27 μmol / min, vs. BYM338: 0.06 (±0.35 μmol / min, p=0.11). The decreasing trend in BAT levels was also observed in week 10. This was also observed in the maglumab group, while no effect on BAT levels was detected in the placebo group. (BYM338: -36.9±44.8mL, vs. placebo: -4.7±18.8mL, p (=0.12).

[0195] Muscle strength. The therapeutic effect of bimaglumab on muscle strength as measured by the leg press is 1 33% at 4 weeks [90% CI -5.5, 87.1; p=0.168], and at the end of the study (2nd At 4 weeks, there was a 45.3% increase [90% CI 3.3, 104.4; p=0.073]. These effects, which showed a tendency, did not reach statistical significance.

[0196] Pharmacokinetics. The pharmacokinetics of bimaglumab in overweight and obese individuals are different from those in lean and obese individuals. This is consistent with observations made in low-body weight individuals, with a threshold of approximately 10 μm for nonlinear clearance loss. The targeted-medium-drug-kinetic (TMDD) profile in g / mL is shown (Figure 5). Loss of clearance may be associated with loss of receptor saturation, at 30 mg / kg A single dose is administered until week 10, when the therapeutic effect on body composition and insulin sensitivity is demonstrated. (71 days) It appeared to saturate the receptors.

[0197] Adverse events. During this clinical trial, serious adverse events (SAEs) and adverse events that could lead to discontinuation of the trial occurred. There were no adverse events (AEs). Acne, muscle cramps, and muscle pain were observed in patients treated with bimaglumab. It was reported in 30% of the population, but not in the placebo-treated group. Diarrhea, muscle weakness, Musculoskeletal rigidity was observed in 10% of the bimaglumab group but not in the placebo group. Upper respiratory tract infections were one of the most frequently reported AEs, but they were not related to the investigational procedure. It was not suspected that this was the case. Anti-drug antibodies (ADAs) were present in 2 out of 10 people after exposure to bimaglumab. It was detected in human subjects and was not neutralized by either ActRIIA or ActRIIB. These ADAs were not associated with unfavorable safety findings or changes in drug exposure. It wasn't there.

[0198] Consideration A single dose of bimaglumab has clinically proven effective in individuals without insulin-resistant diabetes. HbA 1c and resulted in decreased insulin sensitivity. These metabolic effects of bimaglumab were observed without any impact on body weight or changes in lifestyle. , it was associated with significant changes in body composition. The Look AHEAD trial showed that body weight increased by 5- We demonstrated that a 10% weight loss induces clinically significant improvement in cardiovascular risk factors, and that diabetes prognosis is achieved. The Diabetes Prevention Program is for 5% Weight loss was shown to reduce the 5-year risk of developing new type 2 diabetes by 58% (Diabet). es Prevention Program Research Group,200 2) Single-dose bimaglumab showed a significant reduction in total LBM of 2.7% (2 kg ± 1.4). This leads to an increase, while a weight loss regimen with a normal protein intake (1.2g / kg / day) Even with added exercise, the total LBM will at best only maintain the baseline level, while lean body mass will not decrease. No increase has been shown (Longland et al., 2016). Furthermore, Vimag Lumab resulted in a significant and sustained reduction in total FBM of 7.9% (2.3 kg ± 1.7) at week 10. This combination effect results in less resistance, and to the best of our knowledge, it has been found to be effective against any other type of resistance to date. This was not observed with obesity medications. The net result of these changes in body composition is a stronger physique. The neutral weight effect, which is better defined as body type, was the result, but blood glucose parameters and IN The metabolic effects of these changes on surin sensitivity were significant. Bimaglumab is used in obesity. It has a novel mechanism for addressing metabolic complications, particularly the anabolic effect of bimaglumab. To support this, a combination of a calorie-restricted diet and sufficient protein intake is recommended. In addition, in obese patients, bimaglumab provides a longer-lasting effect, in addition to improving body composition parameters. Further clinical trials are needed to evaluate whether the treatment period leads to weight loss.

[0199] Since no effect was observed on fasting blood glucose levels, HbA 1c Improvement is likely due to postprandial blood glucose levels This is thought to reflect a decrease in peripheral insulin sensitivity. This is likely caused by an improvement in skeletal muscle levels. 1c Treatment of The effect was higher than that obtained with metformin or lifestyle interventions (HbA1c in 5 months). (1c decreases by approximately 0.1%) (Diabetes Prevention Program) Research Group, 2002), it was found that liraglutide in a similar population This is equivalent to what was observed with 3.0 mg qd (HbA1c decreased by 0.23% at week 56). (Few) (Pi-Sunyer et al, 2015). Hyperinsulinic euglycemic clamp method And the effect of bimaglumab on insulin sensitivity by IVGTT is, when used Although the indicators used differed slightly among the three clinical trials, they were similar in that they involved calorie restriction in the same population. The effects are equivalent to those of accompanying pioglitazone (45 mg) and liraglutide (1.8 mg). (DeFronzo et al.,2011;Kim et al.,2013;Mat Suda et al, 1999). In diabetic patients, in this population, bimagurum Treatment with b improves insulin sensitivity and clinically significant HbA1c levels. 1c decrease Further, larger-scale clinical trials are needed to evaluate whether the connection is possible.

[0200] Recent human studies have shown how cold exposure and exercise affect brown adipose tissue (BAT) activity. Could this promote it? (Ouellet et al., 2012; Dinas et al.) (2014), and how BAT activity is typically impaired in overweight subjects. This demonstrates the present invention's treatment (Van de Lans et al, 2014). The results of the experiment showed that the thermogenic capacity of BAT in obese and insulin-resistant subjects over time It tends to worsen gradually, and can be detected in just 4 weeks using FDG-PET / CT. Furthermore, such deterioration can be prevented by treating the patient with bimaglumab. This was demonstrated. This beneficial effect of ActRII blockade is supported by preclinical data. As such, this may be the result of activation of mitochondrial oxidative metabolism in BAT (F Ournier et al., 2012). Interestingly, in preclinical studies, intracellular Triglycerides are not only the main fuel for maintaining BAT energy metabolism, but also cold Cold loading has also been shown to lead to almost complete depletion of BAT lipids (Slocum e et al.,2013;Ouellet et al.,2012,Cinti 2009 (Baba et al 2010). In that case, this mechanism is bimaglumab treatment. This may underlie the contraction of BAT volume observed herein in response to this. Therefore, a longer-term treatment with bimaglumab combined with a physical activity program is necessary. Further research is needed regarding the location of this new population, which mainly consists of overweight and obese individuals. Overall, bimagrumab was safe and well-tolerated in the group, and no major safety findings were observed. The adverse events were mild and transient, and based on previous clinical experience with bimaglumab, , acne (especially at the dose levels used in this study), involuntary muscle contractions and muscle pain The results were consistent. The biological explanation for acne remains unclear and will be investigated further.

[0201] An important finding from this clinical trial is the significant positive impact on body composition without affecting weight. This includes changes in body composition. In the absence of exercise and dietary therapy, treatment with bimaglumab is effective in changing body composition. This led to a shift to the "fit fat" phenotype. Furthermore, the body composition in the absence of weight loss... These changes reflected the metabolic effects of weight loss on blood glucose parameters.

[0202] The limitation of this clinical trial is the fact that it is an experimental, exploratory trial involving a small number of participants. The population is heterogeneous in terms of body mass index, including people of normal weight, overweight, and obese. This group was in a state of insulin resistance, and therefore insulin sensitivity and HbA1c were present. 1c The evaluation of the magnitude of the effect of bimaglumab on body fat was limited. In this clinical trial, The effects of bimaglumab on various compartments of the liver were not evaluated, therefore, visceral, subcutaneous, and liver The effect on fat content cannot be discussed. Observed insulin sensitivity The mechanism of sexual improvement has not yet been studied, and insulin levels measured with FBM and clamps have not yet been investigated. A significant relationship was observed between the sensitivity (M / I) and LBM (this was not observed in LBM). Therefore, this is due to a decrease in intramuscular fat mass (Kuhlmann et al, 2003). and / or may be followed by an overall decrease in body fat mass (Figure 3). It is unknown to what extent receptivity is modified by bimaglumab. The inventors have found that We hypothesize that an increase in fat mass could lead to improvements in the function and mobility of these individuals. The effect of the one-legged leg press on muscle strength is not statistically significant or conclusive, but there is a trend. This suggests that iterations with larger sample sizes are needed to evaluate this problem. Further testing is needed. In conclusion, bimaglumab is effective in treating metabolic obesity such as insulin resistance. This may offer a new approach to managing complications. Bimaglumab has a significant effect on body composition. Potentially a novel insulin-sensitizing treatment for type 2 diabetes, mediated through significant effects. There are also available treatments for type 2 diabetes, which tends to increase weight and body fat mass. Unlike other drugs, bimaglumab has the potential to overturn key pathophysiological features underlying type 2 diabetes. It has a sex.

[0203] Example 2: Clinical Trial Clinical trial design BYM338X2211 is used for intravenous bismaggur in overweight / obese patients with type 2 diabetes. A non-verbal, randomized, subject- and principal investigator-investigated study of a 48-week treatment period with B. This was a blinded, placebo-controlled, parallel-group trial. Approximately 60 patients were enrolled and randomized. For patients who consent to voluntary MRI, their liver, internal organs and skin are examined. Lower body fat content is evaluated.

[0204] [Table 3]

[0205] Screening (Day 21 to Day 8) Participants will undergo an on-site screening visit to determine their eligibility for the trial. After screening, subjects whose eligibility for inclusion is confirmed will undergo baseline evaluation. It can be done.

[0206] Planned lifestyle interventions (U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research 2020 08) A 500kcal calorie deficit per day, and US sugar for optimal blood sugar control. The American Diabetes Association (ADA) Follow the guidance diet and consume at least 1.2g / kg / day of protein to support muscle synthesis. This includes dietary counseling for weight loss, along with guidance on calorie intake. Patients also receive counseling on physical activity. You are encouraged to receive the ring and follow the guidelines of the U.S. Department of Health and Human Services (2008). (See SOM). Once eligibility is confirmed, these interventions will be administered at the time of screening. It will begin.

[0207] Baseline (Day -7 to Day -1) Before medication (Day 1), patients who are eligible for inclusion after screening are at baseline. Return to the clinic for evaluation. To facilitate the clinical trial, the patient will be on day 1. You may choose to reside on day -1 in order to complete the baseline assessment before medication is administered.

[0208] Randomization and administration (Day 1) Based on screening and baseline assessment, eligible patients were selected in a 1:1 ratio. The patient will be given either bimaglumab or placebo. Randomization will be performed at baseline. Based on BMI, the following two stratification groups are formed. ●BMI is 28 kg / m² 2 ~33kg / m 2 (Including endpoints), and ●BMI is 33kg / m² 2 Over 40 kg / m 2 The following (including the endpoints).

[0209] The administration of bimaglumab or placebo is performed by intravenous infusion over 30 minutes. Subsequently, an observation period will be established, including safety and tolerability assessments and PK sampling. All evaluations After evaluation, the patient was deemed medically stable and in good general health by the principal investigator. If it is determined that further observation is not necessary, the patient may be discharged from the principal investigator's facility. .

[0210] Treatment period (Day 1 to Day 336) Through the clinical trial, patients will receive background monotherapy according to the eligibility criteria (see selection criteria). The law will continue. All participants will be able to continue receiving treatment for diabetes, background Therapeutic adaptation can be performed.

[0211] Bimaglumab or placebo will be administered in a total of 12 doses, once every 4 weeks. The procedure is performed by intravenous infusion over 0 minutes, followed by a 1-hour observation period. (Bimaglumab) It is administered at a dose of 10 mg / kg based on body weight, and 12 mg / kg for those weighing over 120 kg. With a maximum dose of 00 mg. Placebo is provided as D5W, 5% dextrose solution. ru.

[0212] Through the clinical trial, patients will receive regular checkups regarding diet and physical activity as part of their monthly visits to the facility. Receive periodic monitoring and advice.

[0213] During the treatment period, patients are required to return to the principal investigator's facility approximately every four weeks for medication administration. It is required. During these visits, patients are evaluated for safety, tolerability, pharmacokinetics, and efficacy. It can be done.

[0214] The treatment period ends 4 weeks after the last dose (Day 308 / Week 44).

[0215] Follow-up (Days 364-392) After the completion of the treatment period, the patient will complete their clinical trial visit, which will take place 12 weeks after the last administration of the investigational drug. Until End of Service (EOS), an 8-week follow-up period with regular monitoring of safety and effectiveness. There is a break period (week 52).

[0216] Rationale for setting the clinical trial design (Figure 6) The rationale for setting the main elements of the clinical trial design includes the following: ● Randomization: Reduces the possibility of imbalance in subject characteristics (e.g., age, BMI) between treatment groups. Therefore. ●Stratification: BMI is used for parameters of body composition / weight and HbA1c (internal data). It was selected as a stratification parameter because it is an important predictor of the response. This patient population The expected median BMI in this region is 33 kg / m². 2 (Internal data), and therefore central The two layers above and below the value (including the endpoints) represent the balance between placebo and activity in each layer. This ensures a balanced presentation, that is, layers of roughly the same size between the two groups. ● Blinding of subjects and principal investigators: Treatment allocation, reporting of adverse events, and causal relationships To reduce the risk of bias in evaluation. Furthermore, this design allows for the assignment of treatments. Potential interactions of intentional or unintentional behavioral changes made by known entities. Reduces the entanglement effect. ● Placebo group: Including a placebo provides a comparison group with bimaglumab and allows for a double-blind study. Included to enable the design. ●Lifestyle interventions: In clinical trials using anti-obesity drugs, lifestyle interventions were used as a backup for primary treatment. For the ground, the therapeutic benefits in terms of weight / composition need to be demonstrated. 500kc A daily calorie deficit in AL is a standard approach and induces weight loss over the treatment period. It is predicted that this will occur. This will also enhance the effects of bimaglumab on body composition and weight. The American Diabetes Association (ADA) walking program was obtained by the population in this clinical trial. It is adjusted to suit different types and provides a gentle and easy approach for physical activity. It is known that exercise enhances the effects of bimaglumab on muscle function. This may support the therapeutic benefits of bimaglumab for body composition and weight. ● Appropriate protein intake: This is important for optimal muscle maintenance / growth and calorie deficiency. To compensate for this, a protein intake of 1.2g / kg / day is recommended.

[0217] Standard treatment for diabetes: Patients should continue with the standard treatment for diabetes, which involves blood glucose This enables the evaluation of the therapeutic benefit added by bimaglumab with respect to parameters. Oral diabetes monotherapy is suitable for patients in the early stages of the disease and therefore without significant comorbidities. I support the choice. Monotherapy is limited to metformin or a DPP4 inhibitor. These medications are less likely to affect weight and therefore less likely to confuse test results. It is.

[0218] Rationale for determining dosage / regimen, route of administration, and duration of treatment Rationale for determining dosage In healthy volunteers (HV) and sIBM patients, a 10 mg / kg dose of bima Glumab showed anabolic effects over 4 weeks [CBYM338X2102 (N=6 subjects)] For a maximum of 6 doses, with the same administration interval as CBYM338X2104 (N=47 subjects) [CBYM338X2109 (N=35 people)], maximum 1 year [CBYM338B22 (03 (N=54 IBM patients)) Exposure levels maintained (i.e., greater than 10 μg / mL) It was shown that it provides ). The minimum target exposure threshold for bimaglumab is approximately 10 μg / mL. Yes, and below that concentration, nonlinear clearance is observed, which is due to complete receptor saturation. This suggests loss and loss of target-mediated pharmacokinetics. In clinical trials to date, HV has shown less In both cases, bimaglumab concentrations of approximately 10 μg / mL or higher were observed for 4 weeks, and in sIBM patients for more than 1 year. It is safe, well-tolerated, and shows an increase in thigh muscle mass. The 6-week toxicity study compared human exposure at a steady state of 10 mg / kg with AU For C and Cmax, the NOAEL (300 mg / kg / week) is approximately 300. It showed chronic exposure levels of 2x and 55x.

[0219] In this clinical trial, the dosage was weight-based for patients weighing up to 120 kg. For patients weighing 120kg to 140kg, the maximum dose is 1200mg. It has been proven to reduce the variability of exposure in subjects / patients, and as needed This will be carried out. The magnitude of the impact on the pharmacokinetics, exposure, and safety profile of bimaglumab. Because the effects of body weight and body composition (body fat mass %) relative to lean body mass %) are uncertain, the upper limit The dosage is selected based on body weight exceeding 120 kg. To date, pharmacokinetic data have been obtained for obese individuals. The study was limited to elephants, and included overweight to obese subjects (N=10) with insulin resistance. In a clinical trial conducted with bimaglumab in obese healthy subjects (N=6), the dose-response ratio was The largest elephant recorded weighed 116 kg. The maximum dose of bimaglumab administered to date is 116 kg. Intravenous administration, 3500 mg (30 mg / kg) as a single dose for a maximum body weight of 116 kg. The dose was [amount]. This dose did not indicate excessive exposure, and no safety issues arose. These subjects The upper limit for this drug is to avoid excessive exposure and to ensure safe anabolic effects over a 4-week dosing interval. To maintain the bimaglumab level near the threshold, it is selected. Specifically, The amount of 1200 mg corresponds to 10-8.6 mg / kg for a body weight range of 120-140 kg. The dosage is converted based on body weight in the range of kg, which, for bimaglumab, minimizes overdose. The risk of excess exposure is expected to result in exposure levels within a safe and effective range.

[0220] Basis for setting the treatment period The 48-week treatment period allows for the temporal profile of bimaglumab relative to body fat mass and the most... It is chosen to capture a large effect. The ceiling effect is typically achieved by bimaglumab-induced fat loss. While an increase in volume is observed, the loss of body fat mass continues for 24 weeks, and even up to 64 weeks. Even over this period, it does not appear to reach a plateau (internal data).

[0221] Basis for setting the follow-up period The 8-week long-term follow-up period involved off-control of body fat mass, lean body mass, and blood glucose. Selected to monitor the duration of the therapeutic effect of bimaglumab on the treatment. Last dose The EOS visit, which takes place 12 weeks later, is part of the drug-free period for bimaglumab exposure related to anabolic effects. It covers the period (approximately 8 weeks).

[0222] Rationale for selecting comparator drugs Based on the following rationale, a placebo will be used as the comparator drug in this study. ●A placebo-controlled drug is necessary to maintain a double-blind design. ●Since the change from baseline in the bimaglumab treatment group is the primary determination of efficacy, The placebo group was not intended as a first-line efficacy comparator to bimaglumab.

[0223] Rationale for selecting background therapy This is an anti-obesity clinical trial in patients with T2D, and the primary objective is to assess body composition. This is the effect of bimaglumab. The improvement in blood glucose control occurs as a result of the improvement in body composition. It is possible, but this clinical trial is primarily not a diabetes clinical trial. Therefore, blood glucose control To avoid worsening of the condition, the patient should consistently maintain their background T2D therapy. It is necessary. T2D treatment is limited to monotherapy for the sake of homogeneity of the trial population, and the data can be interpreted. To enable the treatment. Monotherapy includes metformin, first-line treatments, and DPP4 inhibitors. The impact on weight is limited to the class with minimal effect. Improvements in blood glucose control were observed during the clinical trial. If detected, a reduction in antidiabetic treatment may be observed to prevent hypoglycemia.

[0224] treatment Investigational treatment and control drug The LIVI (liquid in the vial) of the investigational drug, BYM338 (bimaglumab) 150 mg, is Prepared by Novartis and supplied to the principal investigator's facility as an open-label bulk drug. It will be administered. The preparation of the investigational drug is detailed in a separate pharmacy manual. Placebo will be administered depending on the facility. This is an injection solution of 5% dextrose (D5W) in water that is supplied.

[0225] [Table 4]

[0226] The investigational drug will be received by a designated person at the clinical trial site, handled safely and appropriately, stored, and managed by the clinical trial manager. It must be stored in a secure location accessible only to the assigned physician and designated staff. Upon receipt, the investigational drug should be stored according to the instructions clearly stated on the drug label. The tube status must be properly monitored, and appropriate temperature logs must be maintained as source data. Appropriate documentation regarding patient-specific dispensing processes must be maintained. Bulk drug labels The instructions are in the local language, comply with the legal requirements of each country, and cover drug storage conditions. It includes information about the patient, but does not include patient information.

[0227] Further clinical trial procedures This clinical trial does not involve any further treatments other than the investigational drug and the control drug.

[0228] Background therapy Metformin or DPP4 inhibitors are used as background for patients to be eligible for clinical trials. It is required as a therapeutic treatment.

[0229] Treatment group Patients will be assigned in a 1:1 ratio to one of the following two treatment groups: Clinical trial procedures are defined as follows: ●BYM338 (bimaglumab) 10 mg / kg, maximum 1200 mg / month (12 doses) ● Monthly placebo (12 doses)

[0230] Efficacy / Pharmacodynamics Pharmacodynamic evaluations are specified below, and are the evaluations specified in the Facility Management Manual (SOM). This includes methods for recording the data. Evaluations are performed and samples are collected at defined points in time.

[0231] Pharmacodynamic (PD) samples are obtained and evaluated for all patients.

[0232] 1. Blood glucose control assessment Fasting insulin and blood glucose levels Fasting blood glucose and insulin are taken at different times.

[0233] HbA1c HbA1c reflects the average glucose concentration over the past three months, and therefore, This provides a useful indicator of bimaglumab's glycemic control over that period. This is a standard endpoint used to evaluate the glycemic effect of certain antidiabetic drugs. HbA1c is a key blood glucose parameter that correlates with a reduced risk of diabetic complications.

[0234] HOMA-IR Patients undergo the Homeostasis Assessment Model for Insulin Resistance (HOMA-IR) and HOMA-I To estimate the degree of insulin resistance using the reciprocal of R, fasting at the time of screening Get tested for insulin and blood sugar levels.

[0235] QUICKI QUICKI is for people with diabetes and elevated fasting blood glucose levels, for example, above 170 mg / dl. In patients, it is considered a better estimate of insulin resistance than HOMA-IR. It is valued (Yokoyama et al 2004). QUICKI is fasting blood glucose HOMA-IR is a derived value of the insulin sensitivity index using insulin levels. This provides further supplementary information to what was obtained (Hrebicek et al 200 2).

[0236] 2. Imaging DXA scan Dual-energy X-ray absorptiometry (DXA) measures total fat and lean body mass (FBM and Body composition, including LBM (Left-Limb Fat) and limb skeletal fat and muscle mass (aFBM and aLBM). It is used to evaluate the changes. The DXA instrument generates and splits into two energies. Using an X-ray source, bone mineral content and soft tissue are measured, and fat and lean body mass are determined from them. Body weight (fat-free mass) (or lean body mass) s)) is estimated. The test is rapid (approximately 5-6 minutes), accurate (0.5-1%), and non-invasive. Therefore, DXA scanners require only 5% accuracy to detect changes in muscle mass. ru.

[0237] Quality assurance is a critical issue in the use of DXA scans to determine body composition. The manufacturer and model of the DXA device should be consistent, and their calibration should be performed through clinical trials. It should be monitored using a standardized scan acquisition protocol and appropriate and immutable The use of scan acquisition and analysis software is essential to achieving consistent results. Similarly, because there is variability in the interpretation of scans, centralized scanning by experienced staff is necessary. It is important to utilize 2D analysis.

[0238] Data collection and processing are handled by imaging CROs supporting clinical trials. This is explained in the Zing Code.

[0239] MRI scan Magnetic resonance imaging (MRI) is used to determine the percentage of fat in the liver (% fat percentage or %FF). , visceral and subcutaneous adipose tissue volume in the abdominal region, as well as paraspinal muscle cross-sectional area and associated fat Evaluate the changes in content (both intermuscular adipose tissue -IMAT and muscle FF content). The images are optimized for water / fat separation and are compatible with the MRI system's capabilities. By using a measuring pulse sequence, the data is acquired in the axial plane.

[0240] Regarding DXA scans, MRI scans are used for imaging to obtain a unified reading. The results are sent to the center and remain with the clinical trial manager until the trial is completed and the database is locked. It remains invisible to doctors, patients, and sponsors. However, in relation to clinical trial analysis No medically significant incidental findings (e.g., tumors) should be included in the clinical trial to ensure appropriate medical care for the patient. This information may be disclosed to the responsible physician. Detailed information can be found in the imaging manual.

[0241] 3.Physical measurements ● Height ● Weight ● Waist circumference ●Temple enclosure ●Ratio of waist circumference to hindquarter circumference ● Body Mass Index (BMI) is calculated (weight (kg) / [height (m)] 2 )

[0242] 4. Measurement of physical function performance Exercise program The ADA Walking Guidelines are recommended. See SOM for further details. I want to be treated that way.

[0243] Timed Chair Stand The timed chair stand test is a short physical performance test. Similar to the components of the ance battery (Patel et al 2014) This refers to the ability of a person to stand up from a chair once, and then multiple times in succession, without using their arms. This is an evaluation. This test does not require advanced skills and can be performed in a clinic or similar setting. It can be carried out within the space of the device. The SOM includes a list of equipment, settings, and instructions. A description of the chair stand test, including the following, is available.

[0244] Handgrip strength test The purpose of this test is to measure the maximum isometric strength of the muscles in the hand and forearm. As a general rule, people with strong hands tend to have strong hands in other areas as well, so this test is often effective in determining strength. It is used as a general test.

[0245] 5. Patient-reported outcomes PRO: The impact of weight on quality of life - Lite The effect of body weight on Quality of Life-Lite (IWQOL-Lite) is To quantitatively assess individuals' perceptions of how their weight affects their daily lives. This is a research method used for weight loss. This method uses indicators that go beyond the realm of physical measurements of weight loss. Therefore, it is particularly useful for verifying the effectiveness of treatments for obesity.

[0246] DTSQ (Diabetes Treatment Satisfaction Questionnaire) The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was first developed in the early 1980s. Currently, it is widely used, especially in clinical trials, but it is also used for routine clinical surveillance. This is available in over 100 languages. The original DTSQ now has a potential ceiling effect. (That is, respondents rate their highest or near-highest satisfaction at baseline, and follow-up Developed to overcome situations where the top may show little or no improvement. To distinguish it from the DTSQ modified version (DTSQc), the status version (D It is referred to as TSQs.

[0247] Analysis of linear variables The primary objective of this clinical trial was to measure bima in relation to body fat mass at weeks 24 and 48 of the treatment period. The objective is to evaluate the effects of glumab.

[0248] variable The primary efficacy variable was the change in body fat mass from baseline at weeks 24 and 48. ru.

[0249] Statistical models, hypotheses, and analytical methods The design of this clinical trial is based on 1) statistical significance in fat mass (superior treatment effect, 10% unilateral reduction). Bell); and 2) Clinical relevance of changes in body fat mass (estimated median treatment effect of ≥5%), This allows for evaluation of effectiveness based on a dual criterion. A 5% weight loss is considered an overweight condition with T2D. It has been shown to lead to clinical benefits in the severe / obese population (Franz et al. (1 2015). Body fat loss equivalent to weight loss is associated with glycemic control in similar populations. Similar clinical benefits are expected, such as those in the field of [specific area].

[0250] Randomization is used to achieve an approximate balance of BMI distributions across the two treatment groups. In addition, BMI categories (28 kg / m2 to 33 kg / m2, over 33 kg / m2) The population is stratified by the threshold of 40 kg / m2 or less. The cutoff value of 33 kg / m2 is used for that population. This represents the predicted median BMI (based on internal data), and therefore, two random The two layers are expected to have similar sizes. The precise determination of the treatment effect in both layers is crucial. To ensure accuracy, a minimum of 10 patients are targeted for inclusion into a smaller group.

[0251] A longitudinal model was used to explain body fat mass over time (time was modeled as a continuous variable). (and) using all data collected from both randomization strata, baseline body fat mass The treatment group and baseline BMI were adjusted using random intercepts and random gradients. The changes in body fat mass at weeks 4 and 48 are estimated from the model. As a supporting analysis... The percentage of patients who achieved at least 5% fat loss by week 24 and week 48 was compared between the treatment group and the treatment group. That's what I'll present.

[0252] Handling / terminating / canceling missing values The above main analytical models are valid under the assumption that data is randomly missing. If the dropout rate exceeds 10% in any group, the missing data will be processed. Therefore, other analytical methods are used to evaluate the sensitivity of the results to different methods.

[0253] Sensitivity analysis To assess the sensitivity of conclusions regarding primary effectiveness for missing data, the dropout rate is predicted. If the measurement is higher, other models (such as pattern mixing models) can be used.

[0254] Analysis of quadratic variables A particularly interesting secondary efficacy variable was the change in HbA1c at weeks 24 and 48. be.

[0255] Blood glucose control and insulin sensitivity (fasting blood glucose and insulin, HOMA- IR (QUICKI) and anthropometric measurements (weight, BMI, waist circumference, waist circumference to hip circumference ratio) And other parameters such as lean body mass (LBM) measured by DXA are other secondary effective It is a sex variable.

[0256] Efficacy / Pharmacodynamics The secondary variable of HbA1c was analyzed in the same way as body fat mass, and the relationship between HbA1c and Vimag Statistical significance of lumab therapy (superior treatment effect, unilateral 10% level); and clinical aspects of this effect The relationship (median treatment effect at 0.5%) is evaluated. A certain model is used to assess HbA1c This explains the changes in HbA1c over time, including the changes at all target points in time (including week 48). The model is used for estimation. The analysis is performed after background antidiabetic drug or dose change. The observed data was cut off. This analysis was observed when background drug / dose adjustments were made. Because it is based on the data (HbA1c, FPG), it is predicted to be unbiased. This increases the likelihood of randomly missing (MAR) censorship data after medication changes. Other adjustments regarding background antidiabetic medications may be considered in the model. As a supporting analysis of the changes in response, an overview of the increase (and decrease) in background antidiabetic medications is provided. Possible. Background changes in antidiabetic drugs include changes in the daily dose and / or a second It is defined as an addition of medication.

[0257] References The entirety of the following references, in particular the definitions and descriptions of sarcopenia, muscle mass, muscle strength, (physical) ability, mobility, and weakness, as well as the definitions and descriptions of clinical trial methods and diagnostic criteria, are incorporated herein by reference. [Table 5] TIFF0007843223000006.tif208151TIFF0007843223000007.tif207149TIFF0007843223000008.tif204149 TIFF0007843223000009.tif202150TIFF0007843223000010.tif196150TIFF0007843223000011.tif168150 The invention described in this specification may encompass the following embodiments. [1] Myostatin or activin or activin receptor antagonist for use in improving body composition in human subjects, with increased lean body mass and decreased body fat mass. [2] Myostatin or activin or activin receptor antagonist for use in the treatment of central fat accumulation in human subjects who are obese, overweight, or have a normal BMI. [3] The aforementioned patient weighs 30 kg / m². 2 Myostatin or activin or activin receptor antagonist for use as described in [1] or [2] above, having a BMI greater than or equal to the above. [4] The aforementioned patient weighs 25 kg / m². 2 More than 30kg / m 2 Myostatin or activin or activin receptor antagonist for use as described above [1] or [2], having a BMI less than [1]. [5] The aforementioned patient weighs 25 kg / m². 2 Myostatin or activin or activin receptor antagonist for use as described above [1] or [2], having a BMI less than [1]. [6] Myostatin or activin or activin receptor antagonist for use as described in any one of the above [1] to [5], which reduces central fat accumulation. [7] Myostatins, activins, or activin receptor antagonists for use in the treatment, prevention, or reduction of obesity or overweight conditions and associated comorbidities. [8] Myostatin or activin or activin receptor antagonist for use as described in [7] above, provided that comorbidities associated with obesity or overweight status are selected from the group of endocrine reproductive disorders such as type 2 diabetes, glucose intolerance, prediabetes, insulin resistance, hypertriglycerides, physical disability, osteoporosis, renal disease, obstructive sleep apnea, sex hormone disorders, polycystic ovary syndrome or hypogonadism, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, gallstones, or altered gonadal hormone profile. [9] Myostatin or activin or activin receptor antagonist for use as described in any one of the above [7]-[8] for the treatment, relief, or prevention of type 2 diabetes.

[10] Myostatin or activin or activin receptor antagonist for use as described in any one of the above [7] to [9], wherein improvement in body composition includes reduction of central fat accumulation.

[11] Myostatin or activin or activin receptor antagonist for use as described above

[10] for the prevention of type 2 diabetes and for the treatment of obesity or overweight conditions.

[12] Myostatin or activin or activin receptor antagonist for use as described above in

[11] for use in improving blood glucose control.

[13] Myostatin or activin or activin receptor antagonist for use as described above

[12] , wherein improved blood glucose control is achieved by improved insulin sensitivity.

[14] Myostatin, activin, or activin receptor antagonist for use in improving glycemic control in patients with type 2 diabetes.

[15] Myostatin or activin or activin receptor antagonist for use as described above

[14] , wherein improved blood glucose control is achieved by improved insulin sensitivity.

[16] Myostatin or activin or activin receptor antagonist for use as described in any one of the above

[14] -

[15] , wherein the patient is obese or overweight.

[17] Myostatin or activin or activin receptor antagonist for use as described above

[16] , which improves the DTSQ score (Diabetes Treatment Satisfaction Questionnaire score), or the IWQOL / IWQOL-lite (Effect of Weight on Quality of Life) score or other PROs associated with obesity and / or diabetes.

[18] A myostatin or activin or activin receptor antagonist for use according to any one of the above [1] to

[17] , wherein the myostatin or activin antagonist is an anti-ActRII receptor antibody.

[19] Myostatin or activin or activin receptor antagonist for use as described above

[18] , wherein the anti-ActRII receptor antibody is bimaglumab.

[20] Bimaglumab is administered in doses of 3 mg / kg or 10 mg / kg, and is used with myostatin, activin, or an activin receptor antagonist for the use described above

[19] .

[21] Bimaglumab administered every four weeks, myostatin or activin or activin receptor antagonist for the use described above

[20] .

[22] A method for improving body composition in a patient requiring such treatment, comprising administering myostatin or an activin antagonist or an activin receptor antagonist, thereby increasing lean body mass and decreasing body fat mass.

[23] A method for treating central fat accumulation in a patient requiring such treatment, comprising administering myostatin or an activin antagonist or activin receptor antagonist, wherein the subject is obese, overweight, or has a normal BMI.

[24] The aforementioned patient weighs 30 kg / m². 2 The treatment method described in any one of the above

[22] to

[23] for persons having the above BMI.

[25] The aforementioned patient weighs 25 kg / m². 2 More than 30kg / m 2 The treatment method described in any one of the above

[22] to

[23] for persons with a BMI less than

[23] .

[26] The treatment method described in any one of the above

[22] to

[23] , wherein the patient has a BMI of less than 25.

[27] A treatment method described in any one of the above

[22] to

[26] that reduces central fat accumulation.

[28] A method for treating, preventing, or alleviating comorbidities associated with obesity or overweight conditions, comprising administering myostatin or an activin antagonist or activin receptor antagonist.

[29] The method according to

[28] above, wherein comorbidities associated with obesity or overweight status are selected from the group of type 2 diabetes, glucose intolerance, prediabetes, insulin resistance, hypertriglycerides, physical disability, osteoporosis, renal disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders such as polycystic ovary syndrome or hypogonadism, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, gallstones, and altered gonadal hormone profile.

[30] The method described in any one of the above

[22] to

[29] for the treatment, prevention or reduction of type 2 diabetes.

[31] A method for improving blood glucose control in patients with type II diabetes, comprising administering myostatin, an activin antagonist, or an activin receptor antagonist.

[32] The method described in

[31] above, wherein improved blood glucose control is achieved by improved insulin sensitivity.

[33] The method according to any one of the above

[30] to

[32] , wherein the patient is obese or overweight.

[34] The method described in any one of the above

[30] -

[33] , which improves the DTSQ score (Diabetes Treatment Satisfaction Questionnaire score), or the IWQOL / IWQOL-lite (IWQOL-lite) score, or other PROs related to obesity and / or diabetes.

[35] The method according to any one of the above

[22] to

[34] , wherein the myostatin or activin receptor antagonist is an anti-ActRII receptor antibody.

[36] The method according to

[35] above, wherein the anti-ActRII receptor antibody is bimaglumab.

[37] The method according to

[36] above, wherein bimaglumab is administered in a dose of 3 mg / kg or 10 mg / kg.

[38] The method according to any one of the above

[36] -

[37] , wherein bimaglumab is administered every four weeks.

Claims

1. A pharmaceutical product comprising an anti-ActRII receptor antibody for the treatment, prevention, or reduction of obesity or overweight conditions in humans, wherein body fat mass is reduced, The aforementioned anti-ActRII receptor antibody binds to human ActRIIB at a Kd of approximately 1.7 ± 0.3 pM. The aforementioned anti-ActRII receptor antibody (i) A light chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 7 or SEQ ID NO: 8, and a heavy chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9; or (ii) CDRs of sequence numbers 1-6 Pharmaceuticals, including

2. A pharmaceutical product comprising an anti-ActRII receptor antibody for the treatment of central adipose tissue accumulation in human subjects, which reduces body fat mass, The aforementioned anti-ActRII receptor antibody binds to human ActRIIB at a Kd of approximately 1.7 ± 0.3 pM. The aforementioned anti-ActRII receptor antibody (i) A light chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 7 or SEQ ID NO: 8, and a heavy chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9; or (ii) CDRs of sequence numbers 1-6 Pharmaceuticals, including

3. The aforementioned human subject was 30 kg / m ２ The above BMI is 25 kg / m². ２ More than 30kg / m ２ A BMI of less than 25 kg / m² ２ A pharmaceutical product according to claim 1 or claim 2, having a BMI of less than 1.

4. A pharmaceutical product comprising an anti-ActRII receptor antibody for the treatment of comorbidities associated with obesity or overweight conditions in human subjects, which results in a decrease in body fat mass, The aforementioned anti-ActRII receptor antibody binds to human ActRIIB at a Kd of approximately 1.7 ± 0.3 pM. The aforementioned anti-ActRII receptor antibody (i) A light chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 7 or SEQ ID NO: 8, and a heavy chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9; or (ii) CDRs of sequence numbers 1-6 Includes, The comorbidities associated with the aforementioned obesity or overweight condition are selected from the group consisting of type II diabetes, glucose intolerance, prediabetes, insulin resistance, hypertriglycerides, physical disability, osteoporosis, renal disease, obstructive sleep apnea, sex hormone disorders, endocrine reproductive disorders such as polycystic ovary syndrome or male hypogonadism, osteoarthritis, gastrointestinal cancer, dyslipidemia, hypertension, heart failure, coronary heart disease, stroke, gallstones, and changes in the gonadal hormone profile, and are used as pharmaceuticals.

5. A pharmaceutical product comprising an anti-ActRII receptor antibody for the treatment of type II diabetes in humans, which reduces body fat mass, The aforementioned anti-ActRII receptor antibody binds to human ActRIIB at a Kd of approximately 1.7 ± 0.3 pM. The aforementioned anti-ActRII receptor antibody (i) A light chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 7 or SEQ ID NO: 8, and a heavy chain amino acid sequence having at least 95% sequence identity with SEQ ID NO: 9; or (ii) CDRs of sequence numbers 1-6 Pharmaceuticals, including

6. The pharmaceutical product according to claim 5, wherein the treatment for type II diabetes improves blood glucose control.

7. The pharmaceutical product according to claim 6, wherein improved blood glucose control is achieved by improved insulin sensitivity.

8. The pharmaceutical product according to any one of claims 1 to 7, wherein the anti-ActRII receptor antibody is bimaglumab.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein the anti-ActRII receptor antibody is administered in a dose of 3 mg / kg or 10 mg / kg.

10. The pharmaceutical product according to any one of claims 1 to 9, wherein the anti-ActRII receptor antibody is administered every four weeks.

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