TW201601741A - Myostatin antagonist for treatment of PEW in ESRD patients - Google Patents

Abstract

Disclosed are methods of treating or modulating protein energy wasting (PEW) in an ESRD patient by administration of a myostatin antagonist.

Description

Myostatin antagonist for PEW in patients with ESRD Cross-reference to related applications

The present application claims the benefit of U.S. Provisional Application Serial No. 61/875,609, filed on Sep.

Instructions for federal government awards for research or development

Not applicable.

Sequence table

This application contains a Sequence Listing which has been filed by EFS-Web and the entire contents of which is incorporated herein by reference. The ASCII copy generated in XXXX of 20XX is called XXXXXUS_sequencelisting.txt, and the size is X, XXX, XXX bytes.

The present invention relates to therapeutic compositions and methods for protein energy expenditure in patients with end stage renal disease.

End Stage Renal Disease (ESRD) has become an increasingly important global public health problem, and it is predicted that hemodialysis populations currently estimated to exceed 2 million people will increase by 7% per year ( Jha et al. 2012 ). Major risk factors for chronic kidney disease (CKD) and subsequent ESRD, such as diabetes, hypertension, obesity, cardiovascular disease, and smoking, are becoming commonplace throughout the world. Patients with ESRD usually undergo maintenance hemodialysis (MHD). Patients with MHD have higher morbidity and mortality; in the United States (US), about one in five will begin after dialysis One year died ( US Renal Data System 2012 ). In addition, lower tolerances for physical activity, lower persistence, and impaired muscle strength reduce the quality of life of patients undergoing hemodialysis ( Storer et al. 2005 ; Lewis et al. 2012 ). Patients with lower muscle mass and lower serum albumin have an increased risk of hospitalization and death ( Kalantar-Zadeh et al. 2001 ; Kalantar-Zadeh et al. 2004 ; Huang et al. 2010 ; Lopes et al. 2010 ; Noori Et al. 2010 ).

As described in more detail below, the syndrome of muscle wasting and malnutrition in ESRD patients is called Protein Energy Wasting (PEW) ( Fouque et al. 2008 ). Although nutritional supplements are often administered according to consensus guidelines ( Ikizler et al. 2013 ), changes in metabolism and catabolism of dialysis and potential uremia make it impossible to correct the pathophysiology of PEW by increasing food intake only ( Carrero et al. 2013 ). PEW increases the risk of infection, cardiovascular complications, weakness, depression and death.

Patients undergoing hemodialysis are also treated with medication to treat complications of kidney disease such as anemia, hypercholesterolemia, opportunistic infections, and calcium-phosphorus constancy abnormalities. Despite the many clinical benefits of using these agents, their ability to improve patient survival has not been demonstrated in clinical trials. For example, the use of erythropoiesis stimulators has been reported to calibrate anemia to a slightly elevated level rather than a decrease in mortality, cardiovascular event rate, and vascular channel thrombosis ratio ( Skali et al. 2011 ). In a recent study, the use of HMG Co-A reductase inhibitors to lower cholesterol levels reduced the rate of aortic atherosclerotic events in patients with advanced CKD, but did not provide significant survival benefit to patients undergoing maintenance dialysis ( Baigent Et al. 2011 ), and in another study did not have a significant effect on fatal or non-fatal cardiovascular events ( Fellstrom et al. 2009 ; Baigent et al. 2011 ). Similarly, the use of calcimimetics to correct parathyroid hyperactivity did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-severe secondary parathyroid gland dysfunction ( Investigators et al. 2012 ). Whether the dialysis dose or dialysis flux rate affects the outcome, the report is also contradictory. One study showed that there was no difference in mortality between high dose and low dose compared to high flux rate and low flux rate ( Eknoyan et al. Human 2002 ); another study showed a significant reduction in all-cause mortality with high efficiency, dilution, and online hemodiafiltration instead of conventional hemodialysis ( Maduell et al. 2013 ).

Patients with MHD who are able to increase muscle mass relative to an increase in total weight are more likely to have a survival benefit even when the overall weight is reduced over time ( Kalantar-Zadeh et al. 2010 ). ESRD patients, including those undergoing maintenance hemodialysis, are in desperate need of other therapies that have the potential to increase muscle mass and improve the multiple outcomes including survival.

At this time, there is no product approved by the Food and Drug Administration (FDA) for the treatment of PEW in MHD. Various approved agents for other indications and nutritional/exercise interventions have been investigated as potential treatments for patients with ESRD and PEW. Examples include human growth hormone (hGH) and hGH analogs; intragastric hormone analogs, anabolic steroids, exercise interventions, and nutritional supplements. This growing literature highlights the lack of effective treatment for this condition.

As described in more detail below, Compound 745 is a fusion protein comprising a human IgGl Fc region and a biologically active peptide that neutralizes myostatin. A myostatin antagonist comprising a peptidomimetic compound 745 and a murine substitute of compound 745 is described in International Patent Application No. PCT/US2003/040781 (WO/2004/058988) and 2006, filed on Dec. 19, 2003. In PCT/US2006/046546 (WO/2007/067616), filed on December 6, the same.

Myostatin is a member of the transforming growth factor-β (TGF-β) family, which is primarily expressed in skeletal muscle and acts as a negative regulator of muscle growth ( Roth et al. 2004 ; McPherron 2010 ). Myostatin in skeletal muscle of uremic rodents is up-regulated ( Sun et al. 2006 ; Zhang et al. 2011 ), and myostatin has been reported in some of the CKD patients ( Verzola et al. 2011 ) but not all The study ( Kopple et al. 2006 ) was up-regulated.

The murine surrogate of Compound 745 increases skeletal muscle mass and muscle strength in a variety of other preclinical models, including normal mice, immunodeficient mice, and MDX mice (Duchenne muscular dystrophy) Model), mice with colon -26 tumors (cancerous body model), hindlimb suspension mice (muscle use/atrophy model) and testicular excision mice (androgen deficiency model) (WO/2004/058988 and WO/2007/067616). In a 5/6 nephrectomized ESRD mouse model, treatment with a murine substitute of Compound 745 reversed weight loss, increased skeletal muscle mass and reduced inflammation ( Zhang et al. 2011 ). In view of the fact that despite the use of dialysis for uremia, the human condition of protein energy expenditure is complex and encompasses the symptoms of malnutrition inflammation and muscle wasting, it is not assumed that 5/6 nephrectomized mice (which do not receive dialysis) will Fully mimic human conditions.

Compound 745 was used in a clinical study to treat cachexia in prostate cancer patients. The patient received 3 mg/kg of Compound 745 subcutaneously (SC) or intravenously (IV) per week. The SC dose of 3 mg/kg per week was associated with a statistically significant change in efficacy endpoint (ie, increased lean body mass, decreased fat mass, and increased muscle size in the lower extremities) compared to placebo ( Padhhi et al. 2014 ). However, the cancer caused by cancer is different from PEW because the treatment with androgen is sometimes effective against cancer-related malignant constitutions but not for PEW.

Disclosed herein is a method of treating protein energy expenditure (PEW) in a human subject with end stage renal disease (ESRD), which is administered by administering a therapeutically effective amount of Compound 745, which is an anti-myostatin. A peptibody consisting of two identical polypeptide chains each consisting of SEQ ID NO: 1. In some embodiments, the human albumin serum albumin content 3.8 g/dL, eg at any time point within 60 days prior to the start of treatment, serum albumin levels 3.8g/dL. In some embodiments, the body mass index (BMI) of the human individual 28kg/m ² . In some embodiments, the method also includes determining a body mass index and/or serum albumin content of the human subject prior to treatment.

Human individuals usually undergo hemodialysis, such as maintenance hemodialysis (MHD), for example weekly. 3 times MHD. The method can include administering to the human subject once a day during at least a portion of the entire course of treatment 10 grams of protein nutritional supplements.

In some embodiments, Compound 745 is administered as a liquid pharmaceutical composition, such as a 10 mM sodium acetate, 9% (w/v) sucrose, and 0.004% (w/v) polysorbate 20 liquid having a pH of 4.75. The pharmaceutical composition is administered in the form. In some embodiments, Compound 745 is administered by an intravenous (IV) infusion. Compound 745 can be obtained, for example, by expressing compound 745 as an insoluble inclusion body in E. coli cells; collecting the cells; lysing the cells; dissolving the inclusion bodies; refolding, concentrating, and chromatography This compound 745 was purified to produce.

In the methods described herein, Compound 745 is administered in a therapeutically effective dose, usually at a dose of from 0.1 mg/kg to 10 mg/kg. In some embodiments, Compound 745 is administered at a dose of 1.0 mg/kg or 2.0 mg/kg or 3.0 mg/kg or 6.0 mg/kg or 10 mg/kg. Compound 745 can be administered, for example, once a week for, for example, 12 weeks. In some embodiments, compound 745 is administered once a week at a loading dose for a first period of time, followed by a maintenance dose for a second period of time greater than the maintenance dose, such as once a week Administration at a dose of 3 mg/kg for 3 weeks followed by administration at a dose of 1 mg/kg for 9 weeks, or administration at a dose of 6 mg/kg for 3 weeks followed by administration at a dose of 2 mg/kg for 9 weeks.

In one embodiment, the method increases the lean body mass (LBM) in a human subject as determined, for example, by Dual-energy X-ray absorptiometry (DXA). Other clinical endpoints include, but are not limited to, increased muscle cross-sectional area as measured by CT, increased lean mass (ALM) of the extremities, and enhanced body function as measured by the Stair climbing power test (SCPT). 6-minute walk test (6-minute walk test, 6MWT ) distance of the increase, with three patients reported results (patient reported Outcome, PRO tool) (renal dialysis quality of life ^{TM (kidney dialysis quality of life TM} , KDQOL TM) - 36 Simple Questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale, and Functional Assessment of Anorexia/Cachexia Treatment (Functional Assessment of Anorexia/Cachexia Treatment) The quality of life measured by at least one of the FAACT) anorexia/cachexia proton scale) is improved. The method of treatment may also cause, for example, at least one biomarker selected from the group consisting of: serum myostatin, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor -α (tumor necrosis factor-α, TNF-α), adiponectin, leptin, resistin, serum lipids and serum albumin.

Also described herein is a kit for treating protein energy expenditure (PEW) in a human subject with end stage renal disease (ESRD) comprising a container comprising Compound 745 and instructions for use.

Figure 1 is a graph showing plasma profiles in a first patient group following administration of Compound 745. The plot of concentration versus time shows a higher plasma concentration (square and triangle) at week 12 compared to week 1 (circle). For week 1, the graph shows values from 8 individuals.

Figure 2 is a graph showing pharmacokinetic modeling, shown by intravenous infusion for 6 weeks at an initial dose of 6 mg/kg per week followed by intravenous infusion at a maintenance dose of 2 mg/kg per week. Simulated plasma concentration-time profile of Compound 745.

definition

Effective amount. The term "effective amount" means the amount of the composition, i.e., an amount effective to ameliorate the symptoms of a disease, such as a PEW in an ESRD patient. An effective amount can be a therapeutically effective amount or a prophylactically effective amount. The effective amount of the pharmaceutical composition will depend, for example, on the condition and goal of the treatment. Therefore, cooked Those skilled in the art will appreciate that the appropriate dosage level for treatment will therefore depend, in part, on the molecule, indication, route of administration, treatment regimen (number and timing of administration), and the size of the patient (weight, body surface) Or organ size) and conditions (age and overall health).

End Stage Renal Disease (ESRD). As described in more detail herein, end stage renal disease is a condition in which the kidneys are no longer able to work to the extent needed by daily life. In the United States, the most common cause of ESRD is diabetes and high blood pressure. ESRD almost always occurs after chronic kidney disease.

Myostatin. Myostatin (also known as the growth factor of GDF-8) is a member of the TGF-β family. Myostatin is known to be a negative regulator of skeletal muscle tissue. Myostatin is synthesized as an inactive preproprotein that is activated by proteolytic cleavage (Zimmers et al., supra (2002)). The precursor protein is cleaved to produce an NH2-terminal inactive pre-domain and a COOH-terminal protein of about 109 amino acids in the form of a homodimer of about 25 kDa, which is a mature, active form (Zimmers et al., supra (2002). )). Mature dimers are now circulating in the blood as inactive latent complexes that bind to the original peptide (Zimmers et al., supra (2002)). Full-length myostatin refers to the full-length human preproprotein sequence described in McPherron et al. PNAS USA 94, 12457 (1997), and related full-length polypeptides including dual gene variants and interspecies homologs (McPherron et al., supra) 1997)). As used herein, the term "myostatin" or "mature myostatin" refers to a mature and biologically active COOH-terminal polypeptide in monomeric, dimeric, polymeric form or other form. "Myostatin" or "mature myostatin" also refers to fragments of biologically active mature myostatin, as well as related polypeptides including dual gene variants, splice variants, and fused peptides and polypeptides. Depending on how it is prepared, myostatin may or may not contain other terminal residues, such as targeting sequences, or methionine and lysine residues, and/or marker or fusion protein sequences.

Protein energy expenditure (PEW). PEW is an ESRD disease as described in more detail below. Symptoms of muscle atrophy and malnutrition.

Individual. The term "subject" or "individual" is a mammal. In one embodiment, the individual is a human.

The singular forms "a", "the", and "the"

Abbreviation and definition list of terms

Protein energy expenditure in ESRD patients

Disclosed herein are methods for treating protein energy expenditure in ESRD patients. Protein energy expenditure or PEW is a syndrome of muscle atrophy and malnutrition in ESRD patients, which results in lower muscle mass, lower serum albumin, lower quality of life, lower tolerance for physical activity, lower persistence, muscle Intensity is weakened, hospitalization risk is increased, hospitalization/bad outcome time is prolonged, and the risk of infection, cardiovascular complications, weakness, depression, and death increases. PEW is not only associated with muscle breakdown and loss of bodily functions, but also with high levels of inflammation and uremia (high blood nitrogen levels) not corrected by dialysis, which can be reduced in the platelet dot method.

The nature of PEW is different from other muscle atrophy syndromes such as cancer-caused cachexia, because treatment with androgen does not work for PEW. Other differences include the cancer stance that is usually the result of inadequate nutrient intake (anorexia), which may occur even in the face of adequate protein intake for uninfected individuals. In PEW, this may be due to abnormal protein hydrolysis of muscles as a key factor in nutrition (not known as nutrient mechanism, not malnutrition, cause loss of muscle mass in kidney failure. Mitch WE J Ren Nutr. July 2006; 16 (3 ): 208-11). In addition, PEW shows inflammation as a large component, and cachexia is not always associated with inflammation.

Serum albumin content

In some embodiments, an ESRD patient with PEW is selected for treatment by measuring serum albumin levels. Serum albumin levels can be determined by any method known to those skilled in the art and/or by any method generally performed in a clinical laboratory. Instance package These include, but are not limited to, the bromocresol green method and the bromocresol purple method. In some embodiments, the method of treatment comprises determining the serum albumin content of a human subject.

In some embodiments, the human albument selected for treatment has a serum albumin content of less than or equal to 3.8 g/dL. In other embodiments, the human albumin selected for treatment has a serum albumin content of less than or equal to 3.7 g/dL or 3.6 g/dL or 3.5 g/dL. In some embodiments, the serum albumin content of the human individual is at any point within 60 days prior to the start of treatment. 3.8g/dL.

Body mass index

In some embodiments, the human individual performing the method of treatment has a lower body mass index (BMI). BMI is determined by dividing body weight (in kg) by the square of height (in meters). In one embodiment, the human individual's BMI is measured by the post-dialysis weight and height of the human individual. 28kg/m ² . In other embodiments, the BMI of a human individual 25 or BMI twenty three. In some embodiments, the method of treatment comprises determining the BMI of a human subject.

Hemodialysis

In some embodiments, an ESRD patient treated with Compound 745 is subjected to hemodialysis. In some embodiments, the ESRD patient is undergoing maintenance hemodialysis (MHD), such as MHD greater than or equal to 3 times per week. In other embodiments, ESRD patients undergo 2, 3, 4, 5, or 6 MHD per week. In other embodiments, ESRD patients undergo hemodialysis daily, for example, 6 hours a day, 6 days a week. In other embodiments, ESRD patients undergo nocturnal hemodialysis, such as 3 to 6 nights per week and between 6 hours and 10 hours each during the patient's sleep. In other embodiments, ESRD patients undergo peritoneal dialysis.

In some embodiments, an ESRD patient treated with Compound 745 is subjected to hemodialysis daily and a nutritional supplement containing at least 10 grams of protein per day. Examples of nutritional supplements include, but are not limited to, nutritional bars, yogurt, and the like.

Clinical endpoint

The methods of treatment disclosed herein result in at least one clinical endpoint improvement in an ESRD patient, such as at least one of the measurements of parameters associated with PEW. In one embodiment, the method increases the lean body mass (LBM) of a human individual. Other clinical endpoints include, but are not limited to, an increase in LBM as measured by dual energy x-ray absorptiometry (DXA), an increase in muscle cross-sectional area as measured by CT, and an increase in lean mass (ALM) of the limbs, by stair climbing dynamic test ( Determination of bodily functions SCPT) enhanced 6-minute walk test (6MWT) distance of the increase, with three patients reported results (PRO tool) (the quality of life of kidney dialysis ^{TM (KDQOL TM)} -36 brief questionnaire, the treatment of chronic diseases The quality of life measured by at least one of the functional assessment-fatigue (FACIT-Fatigue) scale and the functional assessment of anorexia/cachexia constitutional therapy (FAACT). Other clinical endpoints include hospitalization, fractures, and/or reduced cardiovascular events. Other clinical endpoints that may be produced by this method of treatment are described in the examples below.

In other embodiments, the method of treatment results in at least one change in a biomarker selected from the group consisting of: serum myostatin, C-reactive protein, interleukin-6 (IL-6) , tumor necrosis factor-α (TNF-α), adiponectin, leptin, resistin, serum lipids, heme and serum albumin. Other biomarkers are described in the examples below.

The assays and methods for measuring clinical endpoints can be any of the assays and methods well known to those skilled in the art and/or used in clinical laboratory environments. In some embodiments, the assays and methods for measuring clinical endpoints are the same as those described in the examples below.

The clinical endpoint can be measured as an absolute value or as a percentage change over baseline. These changes will typically be statistically significant, such as a bidirectional one-sample t-test with a significance level of a = 0.05. In most cases, an analysis of variance (ANOVA) or an analysis of covariance (ANCOVA) model is used.

Compound 745

A method of treating PEW in an ESRD patient comprises administering a myostatin antagonist compound 745.

Compound 745 is an anti-myostatin peptibody. The peptibody represents a component peptide ("pepti-") and an Fc portion ("body") of an immunoglobulin whose overall structure is similar to an antibody. In this format, the peptide "warhead" interacts with myostatin and inhibits signaling via its receptor. The second domain (Fc component) stabilizes the complex in the body, allowing endothelial cells to undergo endocytosis transfer and recycling via FcRn1 and prolonging the residence time into the therapeutic range of application.

Compound 745 is composed of two identical polypeptide chains that are covalently linked via a disulfide bond. The N-terminal portion of each chain consists of a human IgG1 Fc sequence fused at the C-terminus to an anti-myostatin peptide via a glycine (five glycine acid plus AQ) linker. Each polypeptide chain consists of 255 amino acids starting with the amino acid methionine and ending with glutamic acid. There are three intrachain disulfide linkages between the residues Cys ⁴² -Cys ¹⁰² , Cys ¹⁴⁸ -Cys ²⁰⁶ and Cys ²⁴² -Cys ²⁴⁹ on each polypeptide chain, and in the Cys ⁷ _{chain 1} -Cys ⁷ _{chain 2} and Cys There are two interchain disulfide linkages between the ^10- _{chain 1} -Cys ¹⁰ _{chain 2} . The 510 amino acids that make up the compound 745 molecule yield a theoretical molecular mass of 57,099 Daltons. As a protein expressed by microorganisms, Compound 745 is non-glycosylated.

The 255 residue amino acid sequence of each polypeptide chain of Compound 745 (SEQ ID NO: 1) is shown below. The normal font portion of the sequence indicates the IgG1 Fc sequence. The bold portion indicates the linker sequence of five glycine plus AQ ( GGGGGAQ ; SEQ ID NO: 2). The bold italic portion of the sequence indicates the anti-myostatin peptide ( LADHG QCIRWPWMCP PEGWE ; SEQ ID NO: 3).

Pharmaceutical composition

The methods of treatment described herein comprise administering an effective amount of Compound 745. Compound 745 is typically formulated in the form of a pharmaceutical composition. In addition to compound 745, such pharmaceutical compositions may contain pharmaceutically acceptable excipients, carriers, buffers, stabilizers or other materials well known to those skilled in the art. These materials should be non-toxic and should not interfere with the efficacy of the active ingredients. The exact nature of the carrier or other material may depend on the route of administration, such as oral, intravenous, dermal or subcutaneous, nasal, intramuscular, and intraperitoneal routes.

The pharmaceutical composition for oral administration can be in the form of a tablet, a capsule, a powder or a liquid. Tablets may include a solid carrier such as gelatin or an adjuvant.

Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oil, mineral oil or synthetic oil. A physiological saline solution, dextrose or other sugar solution, or an alcohol such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

In the method of the invention, the pharmaceutical composition can be administered in the form of a solution. The pharmaceutical composition can be administered in the form of an unbuffered solution, for example in the form of saline or an aqueous solution. Alternatively, the pharmaceutical composition may be administered in a suitable buffer solution. The buffer solution can comprise acetate, citrate, alcohol soluble protein, carbonate or phosphate, or any combination thereof. In a preferred embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and volume osmotic concentration of the buffer solution can be adjusted to render it suitable for administration to an individual.

In some embodiments, the buffer solution further comprises an agent for controlling the volumetric osmolality of the solution to maintain the volume osmotic concentration at a desired value, such as a physiological value maintained in human plasma. Solutes that can be added to the buffer solution to control the volumetric osmotic concentration include, but are not limited to, proteins, peptides, amino acids, non-metabolized polymers, vitamins, ions, carbohydrates, metabolites, organic acids, lipids or salts. In some embodiments, the reagent used to control the volumetric osmolality of the solution is a salt. In certain embodiments, the reagent used to control the volumetric osmolality of the solution is sodium chloride or potassium chloride or sodium acetate.

The pharmaceutical composition for intravenous injection, dermal or subcutaneous injection, or injection at the site of the pain will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. . Those skilled in the art will be well able to prepare suitable solutions using, for example, isotonic vehicles such as sodium chloride injection, Ringer's Injection, lactated Ringer's injection. Preservatives, stabilizers, buffers, antioxidants, and/or other additives may be included as needed.

Other components of the liquid pharmaceutical composition include detergents and the like.

In some embodiments, Compound 745 is in the form of a liquid pharmaceutical composition suitable for intravenous (IV) injection, such as 10 mM sodium acetate, 9% (w/v) sucrose, and 0.004% (w/v) poly at pH 4.75. Sorbitol ester 20.

In some embodiments, Compound 745 is provided to the donor (eg, a therapeutic medical professional) in lyophilized form. Subsequently, the lyophilized form is resuspended in a suitable solution prior to administration.

Compound 745 can be administered alone or concurrently or sequentially with other therapeutic combinations.

Dosing method, dosage and treatment plan

The method of treatment comprises administering Compound 745 in an "effective amount" sufficient to demonstrate the benefit to an ESRD patient. The actual amount administered (eg, dose) and the rate of administration will depend on the nature and severity of the PEW being treated. Therapeutic prescriptions (eg, determination of dosage, etc.) are the responsibility of the general practitioner and other physicians, and generally consider the condition to be treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to the physician. Examples of the above techniques and protocols can be found in Remington's Pharmaceutical Sciences, 16th Ed., Osol, A. (ed.), 1980.

It can be administered orally, intravenously, dermally or subcutaneously. In one embodiment, Compound 745 is administered via intravenous infusion. In other embodiments, Compound 745 is administered subcutaneously or intraperitoneally.

The dose can vary depending on the variables listed herein. In some embodiments, the dose is at 0.1 Mg/kg with 100 mg/kg or 0.5 mg/kg and 50 mg/kg or 0.5 mg/kg with 10 mg/kg or 0.1 mg/kg and 10 mg/kg or 1.0 mg/kg with 10 mg/kg or 1.0 mg/kg and 6.0 Between mg/kg. In some embodiments, the dosage is about 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9. Mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg /kg, 2mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/ Kg, 3.0 mg/kg, 3.1 mg/kg, 3.2 mg/kg, 3.3 mg/kg, 3.4 mg/kg, 3.5 mg/kg, 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/ Kg, 4mg/kg, 4.1mg/kg, 4.2mg/kg, 4.3mg/kg, 4.4mg/kg, 4.5mg/kg, 4.6mg/kg, 4.7mg/kg, 4.8mg/kg, 4.9mg/kg 5mg/kg, 5.1mg/kg, 5.2mg/kg, 5.3mg/kg, 5.4mg/kg, 5.5mg/kg, 5.6mg/kg, 5.7mg/kg, 5.8mg/kg, 5.9mg/kg, 6mg/kg, 6.1mg/kg, 6.2mg/kg, 6.3mg/kg, 6.4mg/kg, 6.5mg/kg, 6.6mg/kg, 6.7mg/kg, 6.8mg/kg, 6.9mg/kg, 7mg /kg, 7.1mg/kg, 7.2mg/kg, 7.3mg/kg, 7.4mg/kg, 7.5mg/kg, 7.6mg/kg, 7.7mg/kg, 7.8mg/kg, 7.9mg/kg, 8mg/ Kg, 8.1 mg/kg, 8.2 mg/kg, 8.3 mg/kg, 8.4 mg/kg, 8.5 mg/kg, 8.6 mg/kg, 8.7 mg/kg, 8.8 mg/kg, 8.9 mg/kg 9mg/kg, 9.1mg/kg, 9.2mg/kg, 9.3mg/kg, 9.4mg/kg, 9.5mg/kg, 9.6mg/kg, 9.7mg/kg, 9.8mg/kg, 9.9mg/kg or about 10 mg/kg. Values and ranges in the middle of the recited values are also intended to be part of the invention.

Compound 745 can be administered once a day, or can be administered at 2, 3 or more sub-doses at appropriate intervals throughout the day, or even with continuous infusion or via controlled release formulation delivery. In such cases, the pharmaceutical composition contained in each sub-dose must be correspondingly small to achieve a total daily dose. Dosage units can also be compounded for delivery over several days, for example, using conventional sustained release formulations that provide sustained release of the pharmaceutical compositions over the course of several days. Continuous release Compositions are well known in the art and are particularly useful for delivering pharmaceutical compositions at specific sites. In this embodiment, the dosage unit contains a corresponding plurality of daily doses.

In other embodiments, a single dose of the pharmaceutical composition may be durable so as to be administered at intervals of no more than 3 days, 4 days, or 5 days or no more than 1 week, 2 weeks, 3 weeks, or 4 weeks. Subsequent dose. In some embodiments of the invention, a single dose of the pharmaceutical composition is administered once a week. In other embodiments of the invention, a single dose of the pharmaceutical composition is administered every other month. In one embodiment, Compound 745 is administered once a week.

In some embodiments, Compound 745 is administered once a week at an initial dose for a first period of time, followed by a maintenance dose for a second period of time greater than the maintenance dose. For example, Compound 745 can be administered once a week at a dose of 3 mg/kg for 3 weeks and then administered at a dose of 1 mg/kg for 9 weeks, or at a dose of 6 mg/kg for 3 weeks followed by 2 mg/kg. The dose of kg was administered for 9 weeks.

Set

Also described herein is a kit for treating protein energy expenditure (PEW) in a human subject with end stage renal disease (ESRD) comprising a vial containing Compound 745 and instructions for use. Compound 745 can be in the form of any suitable pharmaceutical composition as described herein, such as a liquid suspension suitable for intravenous (IV) injection. Alternatively, compound 745 can be in a lyophilized state suitable for resuspending prior to use. Instructions for use may include instructions for storage, patient selection, dosage, method of administration, period of use, clinical endpoint, and the like.

Peptide

The methods of treatment described herein comprise administering a peptibosome (i.e., Compound 745) consisting of two identical polypeptides having the sequence SEQ ID NO: 1.

In some embodiments, the compositions useful in the methods of the invention comprise a polypeptide that is less than 100% identical to the amino acid sequences disclosed herein. In some embodiments, the polypeptide is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to the sequences disclosed herein. Or the consistency is between 99% and 100% between.

In the case of two or more amino acid or nucleic acid sequences, the term "percent identical" refers to one of the sequence comparison algorithms described below (eg, BLASTP and BLASTN or available to the skilled person). Other algorithms) or by visual measurement to compare the maximum corresponding to the alignment, two or more sequences or subsequences have a specified percentage of the same nucleotide or amino acid residue. Depending on the application, the percent identity may exist in the region of the sequence being compared (eg, the functional domain) or in the full length of the two sequences to be compared.

In the case of sequence comparisons, typically one sequence serves as a reference sequence for comparison with a test sequence. When using the sequence comparison algorithm, the test and reference sequences are entered into the computer, subsequence coordinates are specified if necessary, and the program parameters of the sequence algorithm are specified. Subsequently, based on the specified program parameters, the sequence comparison algorithm is used to calculate the percent sequence identity of the test sequence relative to the reference sequence.

The optimal sequence alignment for comparison can be performed, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2: 482 (1981), by Needleman & Wunsch, J. Mol. Biol. 48: The homology alignment algorithm of 443 (1970), by the similarity search method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85: 2444 (1988), by computerization of such algorithms Protocol (Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., GAP, BESTFIT, FASTA, and TFASTA in Madison, Wis.), or by visual inspection (see generally Ausubel et al., see Follow below).

One example of an algorithm suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al, J. Mol. Biol. 215: 403-410 (1990). Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov/).

Variant

The compositions described herein also encompass variants of the polypeptides described herein. As used herein, the term "variants" refers to a polypeptide that inserts, deletes or substitutes one or more amino acid residues in the original amino acid sequence and retains at least a portion of the functions of the polypeptides described herein. As used herein, fragments of a polypeptide are included within the definition of "variant." It should be understood that any given peptide or peptid may contain one or two or all three types of variants. Inserted and substituted variants may contain natural amino acids as well as non-naturally occurring amino acids or both. Variants may include, for example, a polypeptide comprising a leader sequence or a signal sequence; a polypeptide having, for example, another amine terminal residue of Met 1 or Lys 2; a polypeptide having a display marker such as a histidine acid; and a polypeptide expressed as a fusion protein .

Variants of the polypeptides described herein can include amino acid substitutions. 20 conventional (naturally occurring) stereoisomers of amino acids (eg D-amino acids), such as α-, α-disubstituted amino acids, N-alkylamino acids, lactic acid and others The non-naturally occurring amino acid of the amino acid can also be a suitable component of the polypeptide of the invention. Examples of non-naturally occurring amino acids include, for example, aminoadipate, beta-alanine, beta-alanine, aminobutyric acid, pipecolic acid, aminocaproic acid, amine heptanoic acid, amine groups Isobutyric acid, aminopimelic acid, diaminobutyric acid, alkane, diaminopimelic acid, diaminopropionic acid, N-ethylglycine, N-ethyl aspartate, hydroxyl Amino acid, hydroxy lysine, hydroxyproline, iso-chain, leucine, N-methylglycine, sarcosine, N-methylisoleucine, N-methyl Proline, n-proline, ortho-amine, ornithine, 4-hydroxyproline, γ-carboxy glutamic acid, ε-N, N,N-trimethyl lysine, ε-N - Ethyl lysine, O-phosphoric acid, N-acetamidine, N-methyl methionine, 3-methylhistamine, 5-hydroxy lysine, σ -N-methyl arginine and other similar amino acids (eg 4-hydroxyproline).

Naturally occurring residues can be classified into (overlapping) categories based on general side chain properties: 1) neutral hydrophobicity: Met, Ala, Val, Leu, Ile, Pro, Trp, Met, Phe; 2) Neutral polarity: Cys, Ser, Thr, Asn, Gln, Tyr, Gly; 3) Acidity: Asp, Glu; 4) Basicity: His, Lys, Arg; 5) Residues affecting chain orientation: Gly, Pro; and 6) aromatic: Trp, Tyr, Phe.

Substitution of naturally occurring amino acids can be conservative or non-conservative. Conservative amino acid substitution involves exchanging one member of one of the above categories into other members of the same class. Conservative changes may encompass non-conventional amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. Such non-conventional amino acid residues include peptide mimetics and other reversal or reversal forms of the amino acid moiety.

Instance

The following are examples of specific embodiments for carrying out the invention. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way. Efforts have been made to ensure the accuracy of the numbers used (eg, amounts, temperatures, etc.), but should allow for some experimental error and bias.

The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the skill of the art. These techniques are fully explained in the literature. See, for example, TEC Reighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); ALLehninger, Biochemistry (Worth Publishers, Inc., current edition); Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd ed., 1989). Methods In Enzymology (S. Colowick and N. Kaplan, ed., Academic Press, Inc.); Remington's Pharmaceutical Sciences , 18th ed. (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry, 3rd ed. (Plenum Press) Volumes A and B (1992).

Example 1: Compound 745. Performance and preparation

International Patent Application No. PCT/US2003/040781 (WO/2004/058988), filed on Dec. 19, 2003, and PCT/US2006/046546 (WO/2007/067616, filed on Dec. 6, 2006) As described in the above, compound 745 is expressed as an insoluble inclusion body by E. coli fermentation (for example, pAMG-Fc fusion construct in E. coli strain 2596).

Typical fermentations were carried out for 12 hours to 16 hours after induction, followed by collection of cells using a disc stack centrifuge. The cells are lysed by high pressure homogenization to separate inclusion bodies. After washing and centrifugation, the resulting double-washed inclusion body slurry (DWIB) was stored at -30 ° C ± 10 ° C until purification.

After dissolving DWIB, Compound 745 was refolded in a solution containing urea, glycerol, arginine, and redox to cysteine/cystamine. After refolding, the product was concentrated and the refolding reagent was removed by means of ultrafiltration and diafiltration (UF/DF) methods. The diafiltered product is acidified and then clarified. The product is then purified via three different chromatographic steps: two anion exchange (Q Sepharose Fast Flow) columns (one of which operates in a flow-through mode and one in a combined and lysate mode), and HIC (Butyl Sepharose Fast Flow) column. The product was then further concentrated and diafiltered into the formulation buffer by the UF/DF method. The formulated product was then filtered through a 0.2 [mu]m filter into a bulk container and frozen at -30 °C ± 10 °C.

An additional chromatography step is added to the purification method used in the clinical drug method to remove impurities associated with the host cell.

Formulation

The final dose formulation of 30 mg/mL of Compound 745 was 10 mM sodium acetate, 9% (w/v) sucrose, 0.004% (w/v) polysorbate 20 at pH 4.75.

Drug supply and storage

Compound 745 was stored in a non-frost freezer set between -20 ° C and -70 ° C. A range of -20 (+5) ° C to -70 (-10) ° C can be accepted to accommodate fluctuations in the freezer temperature. Exposure of the vials to higher temperatures and vigorous shaking of the vials should be avoided as such conditions may result in impaired performance and structural integrity of Compound 745.

Example 2: Treatment of end stage renal disease with protein energy expenditure

PEW in ESRD patients was treated by administration of anti-myostatin peptidic compound 745. Usually serum albumin content of patients 3.8 g/dL, eg at any time point within 60 days prior to the start of treatment, serum albumin levels 3.8g/dL. In addition, the patient's body mass index (BMI) 28kg/m ² . Usually patients are performed weekly 3 maintenance hemodialysis (MHD). Compound 745 was administered as a liquid pharmaceutical composition containing 10 mM sodium acetate, 9% (w/v) sucrose, and 0.004% (w/v) polysorbate 20 at a pH of 4.75, and by intravenous (IV) Infusion of investment.

Compound 745 is administered once a week at a therapeutically effective dose for 12 weeks: once weekly at 3 mg/kg for 12 weeks; once weekly at a dose of 3 mg/kg for 3 weeks followed by a dose of 1 mg/kg Administration for 9 weeks; or administration at a dose of 6 mg/kg for 3 weeks followed by administration at a dose of 2 mg/kg for 9 weeks.

This method increases the lean body mass (LBM) of the patient as determined, for example, by dual energy X-ray absorptiometry (DXA). Other clinical endpoints included an increase in muscle cross-sectional area as measured by CT, an increase in lean mass in the limbs (ALM), an increase in body function as measured by the Stair Climb Dynamic Test (SCPT) and an increase in the distance of the 6-minute walk test (6MWT). three kinds of patients report results (PRO tool) (quality of life of renal dialysis ^{TM (KDQOL TM)} -36 simple questionnaire, functional evaluation of the treatment of chronic diseases - fatigue (FACIT-fatigue) scale, and anorexia / cachexia treatment The quality of life measured by at least one of the functional assessment (FAACT) anorexia/cachexia proton scale) is improved. The method also results in a change in at least one biomarker selected from the group consisting of serum myostatin, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) ), adiponectin, leptin, resistin, serum lipids and serum albumin.

Patient selection

Eligible patients are men and women between the ages of 18 and 85 who have the following conditions: have ESRD; receive outpatient maintenance hemodialysis for at least 6 months before treatment begins; receive within 12 weeks prior to participation Kt/V 1.2 appropriate dialysis twice; average weekly 3 times of dialysis; suffering from serum albumin content 3.8g/dL and body mass index (BMI) Low albuminemia and low BMI as defined by 28kg/m ² ; and life expectancy 6 months.

Exclusion criteria

The patient may (but may not) exclude treatment for at least one of the following reasons: there is a central venous catheter indwelling; medical professionals determine that current medical conditions (such as severe neuropathy, limb resection, use of walking stents or other conditions) will The ability to interfere with the test (such as stair climbing) required by the individual to conduct the study endpoint; diameter 1cm non-healing ulcer / sore lasts 4 months, or a history of 踝/肱 index <0.9; active infection requiring oral (IV) antibiotics or requiring oral antibiotics within 2 weeks of starting treatment within 4 weeks of starting treatment Major surgery within 3 months prior to initiation of treatment, minor surgery within 4 weeks of initiation of treatment, or dialysis channel change/angioplasty/replacement within 2 weeks of initiation of treatment; within 2 years of initiation of treatment A history of kidney transplantation (whether or not it functions) (however, if the graft has been removed, the patient will be considered eligible if the original transplant occurs), or a kidney transplant is planned within 6 months of starting treatment. Currently treated with an appetite stimulant, including anabolic steroids or growth hormone (if the male individual is hypogonadic, it can accept physiological testosterone replacement) - the dose for the first 3 months of screening must be stable and expected during treatment No change); difficulty swallowing, risk of aspiration or difficulty swallowing food or fluid; myocardial infarction or unstable cramps within 6 months of starting treatment, or congestive heart failure during screening (New York Heart Association level (New York Heart Association Class) Class III or higher); high liver function test values, including total bilirubin 1.5× upper limit of normal (ULN) (unless the individual has Gilbert's disease recorded), aspartate transaminase (AST) or alanine transaminase (ALT) 3.0×ULN; platelet count <80×10 ⁹ /L (80,000/mm ³ ); heme <8.5g/dL (85g/L; 5.3mmol/L); white blood cell count <3×10 ⁹ /L (3000/ Mm ³ ); positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody and abnormal liver function test results unacceptable to researchers and sponsors; HIV infection or AIDS; history of neoplasms (excluding non-melanoma skin cancer) And 30% recurrence within 12 months; 4 weeks prior to initiation of treatment or 5 half-lives (whichever is longer) using any research product; prior treatment with any research device within 4 weeks Pregnancy (if female) by positive human chorionic gonadotropin (HCG); if the HCG test is uncertain, use follicle-stimulating hormone (FSH) test to confirm; current breastfeeding (female); a person who is unwilling to use a probable method of sexually active contraceptives (ie, less than 1% of pregnancies each year) who have a fertility possibility or a female spouse who has a fertility possibility, Contraceptive methods such as implants, injectables Combination of oral contraceptives, some intrauterine contraceptive devices (IUD), abstinence or spouse resection of the vas deferens; unwilling to use effective contraceptives during the study with female spouses, and/or when treated with Compound 745 and Three months after the last dose, they are reluctant to avoid donating sperm; there is ascites or pleural effusion requiring medical intervention; there is a history of portal vein bypass or extensive hepatectomy (more than one liver segment).

Required nutritional supplements

When taking treatment, the individual takes one of the daily doses 10 grams of protein oral supplements. The supplement may be any brand of oral stick or supplement containing the desired amount of protein.

Compound 745

Compound 745 was administered weekly by intravenous (IV) infusion for 12 weeks. Three regimens were used: weekly administration at 3 mg/kg for 12 weeks; weekly administration at 3 mg/kg for 3 weeks followed by 1 mg/kg for 9 weeks; or 6 mg/kg Dose The administration was continued for 3 weeks and then administered at a dose of 2 mg/kg for 9 weeks.

The drug is administered after dialysis. After dialysis, the infusion was performed via IV venous needles at an IV push rate of 6 mL/min.

Clinical endpoint: efficacy assessment

After treatment, the clinical endpoint is measured, for example, for efficacy evaluation. For purposes of overview and as described in more detail below, this may include measuring LBM by DXA, measuring muscle cross-sectional area by CT, measuring muscles, measuring body by SCPT and 6-minute walk test (6MWT) Function, measuring the biomarker (cytokine, lipid and myostatin) content of the entire treatment process, and using 3 PRO tools (KDQOL ^TM -36 short questionnaire, functional assessment of chronic disease treatment - fatigue [FACIT- Fatigue] scale, and functional assessment of anorexia/cachexia treatment [FAACT] anorexia/cachexia proton scale) measures changes in quality of life. Efficacy was assessed throughout the 12-week treatment and 8 weeks post-treatment monitoring. In general, the evaluation is performed on the time of administration of Compound 745 or on other days of the same week for convenience. However, due to individual fatigue on the expected dialysis day, the muscle function test (SCPT and 6MWT) should be performed on a non-dialysis day, and because the edema accumulation may confuse the scan analysis, the DXA/CT scan should be performed within 30 hours of the most recent dialysis completion.

Pharmacokinetics: Pharmacokinetics The amount of compound 745 in a blood sample is determined by a central laboratory. The following parameters were estimated from blood content using standard non-compartmental model pharmacokinetic methods: terminal half-life, clearance, mean residence time, volume of distribution, and steady-state volume.

Assessment based on medical history: Medical history information includes general medical history, history of diabetes, history of dialysis, duration of dialysis, history of PDW reduction, and type of vascular access for dialysis (arteriovenous fistula versus arteriovenous graft) and baseline scores for mCCI.

Normalized Protein Catabolic Rate (nPCR): The protein catabolic rate (PCR) quantifies the catabolism of proteins and can be derived from the increase in urea production rate between dialysis. Divide by individual by PCR The weight-calculated nPCR correlates with dietary protein intake, and studies have shown that moderate protein uptake produces a positive nitrogen balance without the need to increase the dialysis dose (Grupe et al. 1983). PCR was estimated using BUN according to the method of Randerson (Keshaviah et al. 1991) and nPCR was calculated based on the PCR and the most recent PDW (Uribarri et al. 1997) using the following equation: PCR (grams per day) ) = 5.02 × (BUN (in mg/min) + 3.12) and nPCR = PCR/PDW. The nPCR is automatically calculated on the eCRF based on the reported values of BUN and PDW.

Muscle function test: SCPT and 6MWT were tested using two muscle functions. SCPT and 6MWT were performed on non-dialysis days due to individual fatigue on the expected dialysis day (Majchrzak et al. 2005).

Myostatin, cytokines, and adipocyte hormone biomarkers: Since Compound 745 inhibits myostatin, serum myostatin levels are monitored to determine individuals treated with Compound 745 compared to placebo-treated individuals. Whether the serum myostatin content is affected differently. In addition, the levels of cytokines such as C-reactive protein, interleukin-6 and tumor necrosis factor alpha, as well as cellular fat hormones such as adiponectin leptin and resistin are monitored to determine treatment with placebo. Whether the levels of cytokines and adipocyte hormones are differently affected in individuals treated with Compound 745 compared to individuals.

Serum lipids: The serum lipid levels of the patients were monitored to determine if serum lipid levels were differently affected in individuals treated with Compound 745 compared to placebo-treated individuals.

Serum albumin: serum albumin levels below 4.0 g/dL are associated with increased mortality in patients with ESRD. Therefore, serum albumin levels were monitored to determine if serum albumin levels were differently affected in individuals treated with Compound 745 compared to placebo-treated individuals.

Lept body mass (LBM): determined by dual energy X-ray absorptiometry LBM, limb lean mass (ALM) and fat body mass.

Efficacy assessment Body weight after dialysis

PDW is the individual body weight measured at the end of dialysis.

Standardized protein catabolic rate (nPCR)

Protein catabolic rate (PCR) quantifies protein catabolism and can be derived from an increase in urea production rate between dialysis. The nPCR calculated by dividing the individual by the weight of the individual is related to dietary protein intake, and studies have shown that moderate protein uptake produces a positive nitrogen balance without the need to increase the dialysis dose ( Grupe et al. 1983 ). In this method of treatment, PCR should be recorded using values provided by local laboratories. Every effort should be made to maintain the results of the nPCR treatment at baseline and in the study to avoid variability. In the case where nPCR is not reported in the local laboratory, nPCR will be estimated according to the following formula ( Jindal et al. 1988 ): nPCR = 0.22 + (up to 24 in dialysis of 0.036 x BUN) / (dialysis interval)

For example, in the case where BUN is 80 before dialysis and BUN is 20 after dialysis, and the dialysis interval is 44 hours (for example, from the end of one dialysis to the interval of 44 hours from the start of the next dialysis), the nPCR is calculated to be 1.40. G/kg/day.

Body composition

LBM, ALM and fat body mass were determined by DXA using standard methods.

Thigh muscle cross-sectional area

The thigh muscle cross-sectional area was determined by CT using standard methods.

Muscle function test

SCPT and 6MWT were tested using two muscle functions. SCPT and 6MWT must be performed on non-dialysis days due to individual fatigue on the expected dialysis day ( Majchrzak et al. 2005 ).

Stair climbing power test

SCPT measurements are used to climb the vertical steps as quickly and safely as possible without running, and are calculated using the individual's weight, the time required for climbing, and the distance covered ( Bean et al. 2007 ). The use of an opto-electronic stepping pad that interfaces to a timer that automatically records the interval between individual steps of the individual facilitates the timing of the test. Calculate the power using the following equation:

1. Speed (v) = total vertical distance (d) / time required to climb 10 steps (t)

2. Strength = individual mass (m) × gravity acceleration (9.81m/sec ² )

3. Power = (power) × (v)

6 minute walk test

The 6MWT measures the distance that an individual travels over a flat surface over a 6 minute period ( G Guyatt et al. 1984 ; Hamilton et al. 2000 ). 6MWT was performed according to guidelines from the American Thoracic Society (ATS) for the use of 6MWT for the assessment of patients with heart disease or lung disease ( Brooks et al. 2003 ). For ESRD patients who may have complicated heart disease or lung disease and have a reduced overall level of physical activity, most of these criteria are appropriate and appropriate.

Patient report result (PRO)

If the PRO is evaluated on the same day as the body function test (6MWT or SCPT), the PRO tool (KDQOL ^TM -36, FAACT Anorexia Body Mass Scale, or FACIT-Fatigue Scale) should be introduced prior to the first body function test.

Kidney disease quality of life questionnaire

KDQOL ^TM -36 to hemodialysis patients already in progress in the verification of the 36 survey (Korevaar et al. 2002).

Functional assessment of anorexia and cachexia constitution - anorexia / cachexia proton scale

The FAACT Anorexia/Carcinogenic Proton Scale for anorexia and cachexia is a quality of life tool that contains 12 questions about appetite and feelings about food and diet. This tool has been validated in patients with cancer ( Ribaudo et al. 2000 ; Chang et al. 2005 ).

Functional Assessment of Chronic Disease Therapy - Fatigue Scale

The FACIT-Fatigue Scale is a quality of life tool that contains 13 questions about general fatigue and its impact on daily life. FACIT-fatigue is already associated with rheumatoid arthritis ( Cella et al 2005 ), chronic immune thrombocytopenia ( Signorovitch et al. 2011 ), paroxysmal nocturnal hemoglobinuria ( Weitz et al. 2013 ), and systemic erythema It was confirmed in patients with lupus ( Lai et al. 2011 ).

Medical resource utilization

Determine the utilization and duration of use of medical resources. The following resources were taken: hospitalization; admission to the ICU in hospital; access to the emergency room; use of mobility aids (walkers, staff, wheelchairs); other medical clinics.

Biomarker Myostatin, cytokines and cell fat hormones

Clinical laboratory analysis of myostatin, CRP, IL-6, TNF-α, adiponectin, leptin, and resistin was performed using standard assays.

Serum albumin

Serum albumin levels below 4.0 g/dL are associated with increased mortality in patients with ESRD ( Lopes et al. 2010 ; Mazairac et al. 2011 ; Molnar et al. 2011 ). Serum albumin will be measured as part of the standard clinical chemistry group and every effort should be made to standardize the collection time to consistently assess albumin before or after dialysis. Serum albumin is measured using standard methods including, but not limited to, bromocresol green or bromocresol purple analysis.

Example 3: Basic pharmacokinetics of Compound 745

Compound 745 was administered to ESRD patients ("Group 1A" n=8, active agent: placebo for randomization 3:1) once weekly at a dose of 3 mg/kg per week using the method described in Example 2. Or placebo) for 12 weeks.

The plasma concentration of Compound 745 is shown in Figure 1 (FIG. 1). The basic PK data for all individuals in group 1A (n=8) after initial administration showed a _Cmax of 63.1 ± 9.8 μg/mL in the first week, a half-life of 243 ± 261 hours, and an AUC _0-t of 2480 ± 128 h. ×μg/mL. PK data from 2 individuals were obtained at week 12 after 12 weeks of weekly dosing, showing an average _Cmax of 110 μg/mL, an average half-life of 321 hours, and an average AUC _0-t of 22400 h x μg/mL. . The 12-week _{Cmax of the} steady state and the exposure exceeded the expected 3 mg/kg dose per week before the study. Based on a comparison of the AUC values for Week 1 and Week 12 and the continued increase in AUC observed during 12 weeks, exposure was increased by a factor of 9 due to lower than expected clearance.

745 compounds have higher exposure and longer half-life than expected from previous clinical studies based on individuals without kidney damage. This information is consistent with recent reports in the literature ( Wu and Sun, 2014 ), which indicates that other peptibodies structurally similar to compound 745 undergo renal clearance, and that clearance is reduced and half-life is prolonged in patients with renal impairment.

As shown in Figure 2 (FIG. 2), PK modeling based on Group 1A data supports the use of a starting dose to optimize the steady state, such as a weekly dose of 6 mg/kg. And 3 times) followed by weekly administration of 2 mg/kg as described in the maintenance protocol. Thus, as described in Example 2, the patient received an initial dose of 6 mg/kg of Compound 745 per week for 3 weeks, followed by a maintenance dose of 2 mg/kg per week. This dosing regimen will result in an exposure similar to that of Group 1A, and it is expected that steady state exposure will be established after about 3 weeks of dosing.

Compound 745 can also be administered to a patient by administering 3 mg/kg of Compound 745 per week for 3 (starting) doses followed by a 1 mg/kg (maintenance) dose per week. PK modeling indicates that this dosing profile in an individual with ESRD is expected to produce a steady state _Cmax as shown in Table 1. Subcutaneous (SC) doses of 3 mg/kg per week were associated with statistically significant changes in efficacy endpoints compared to placebo (ie, increased lean body mass, decreased fat mass, and increased muscle size in lower limbs) ( Padhhi et al.) .2014 ).

While the invention has been particularly shown and described with reference to the preferred embodiments of the embodiments of the present invention, it is understood that various changes in form and detail may be made therein without departing from the spirit and scope of the invention. .

All references, issued patents and patent applications are hereby incorporated by reference in their entirety in their entirety in their entirety in the entireties in

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<110> US Commodity Special Biotherapy Co., Ltd.

<120> Myostatin antagonists for PEW in patients with ESRD

<130> 29956-26100 PCT

<140> 103131076

<141> 2014-09-09

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<151> 2013-09-09

<160> 3

<170> PatentIn version 3.5

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<213> Artificial sequence

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<223> Description of the artificial sequence: synthetic peptide

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Claims (25)

A method of treating protein energy wasting (PEW) in a human individual patient in need of End-Stage Renal Disease (ESRD), comprising administering a therapeutically effective amount of Compound 745, each of which is SEQ ID NO: 1 is an anti-myostatin peptone composed of two identical polypeptide chains composed of SEQ ID NO: 1. The method of claim 1, wherein the human albumin serum albumin content 3.8 g/dL, the serum albumin content was determined by bromocresol green or bromocresol purple analysis. The method of claim 1, wherein the human albumin serum albumin content is at any time point within 60 days before the start of treatment 3.8 g/dL, the serum albumin content was determined by bromocresol green or bromocresol purple analysis. The method of any of the preceding claims, wherein the body mass index (BMI) of the human individual is based on the post-dialysis weight and height of the human individual. 28kg/m ² . The method of any of the preceding claims, further comprising determining a body mass index and/or serum albumin content of the human subject prior to treatment. The method of any of the preceding claims, wherein the human subject is undergoing maintenance hemodialysis (MHD). The method of any of the preceding claims, wherein the human subject is performed weekly 3 times MHD. The method of any of the preceding claims, further comprising administering to the human subject once a day during at least a portion of the entire treatment period 10 grams of protein nutritional supplements. The method of any of the preceding claims, wherein the compound 745 is in the form of a pH of 4.75. A liquid pharmaceutical composition containing 10 mM sodium acetate, 9% (w/v) sucrose, and 0.004% (w/v) polysorbate 20. The method of any of the preceding claims, wherein compound 745 is administered by intravenous (IV) infusion. The method of any of the preceding claims, wherein the compound 745 is produced by expressing the compound 745 as an insoluble inclusion body in E. coli cells; collecting the cells; lysing the cells The cells are solubilized; the compound 745 is refolded, concentrated and chromatographed. The method of any of the preceding claims, wherein compound 745 is administered at a dose of from 0.1 mg/kg to 10 mg/kg. The method of any one of the preceding claims, wherein the compound 745 is administered at a dose of 1.0 mg/kg to 10 mg/kg or 1.0 mg/kg or 2.0 mg/kg or 3.0 mg/kg or 6.0 mg/kg or 10 mg/kg. versus. The method of any of the preceding claims, wherein compound 745 is administered once a week. The method of any one of the preceding claims, wherein compound 745 is administered once a week for a first period of time with a loading dose, and then administered at a maintenance dose for a second period of time greater than the maintenance dose. The method of any of the preceding claims, wherein the compound 745 is administered once a week at a dose of 3 mg/kg for 3 weeks and then administered at a dose of 1 mg/kg for 9 weeks, or at a dose of 6 mg/kg. It was continued for 3 weeks and then administered at a dose of 2 mg/kg for 9 weeks. The method of any of the preceding claims, wherein the method increases the lean body mass (LBM) of the human individual. The method of any of the preceding claims, wherein the method produces at least one clinical endpoint in the human individual, the endpoint being selected from the group consisting of: dual energy X-ray absorptiometry (Dual-energy X-ray) Absorptiometry, DXA) Increased LBM, increased muscle cross-sectional area as measured by Computed Tomography (CT), increased appendicular lean mass (ALM) as measured by DXA, climbed by stairs The body function of the Stair climbing power test (SCPT) was enhanced, and the distance of the 6-minute walk test (6MWT) was increased. Three patient report results (Patient Reported Outcome, PRO tool) (kidney dialysis) were used. the quality of life ^{TM (Kidney Dialysis quality of LifeTM,} KDQOL TM) -36 simple questionnaire, functional evaluation of the treatment of chronic diseases - fatigue (functional assessment of chronic illness therapy- fatigue, FACIT-fatigue) scale, and anorexia / evil In the Functional Assessment of Anorexia/Cachexia Treatment (FAACT), the anorexia/cachexia proton scale Improve the quality of life of at least one assay. The method of any of the preceding claims, wherein the method results in a change in at least one biomarker selected from the group consisting of: serum myostatin, C-reactive protein, interleukin-6 (interleukin-6) , IL-6), tumor necrosis factor-α (TNF-α), adiponectin, leptin, resistin, serum lipids and serum albumin. A kit for treating protein energy expenditure (PEW) in a human subject with end stage renal disease (ESRD), comprising a container containing compound 745 and instructions for use. A method of treating protein energy expenditure (PEW) in a human individual patient in need of end stage renal disease (ESRD) comprising administering a therapeutically effective amount of Compound 745, which is the same two of each consisting of SEQ ID NO: An anti-myostatin peptone composed of a polypeptide chain, wherein: the serum albumin content of the human individual 3.8 g/dL and maintenance hemodialysis (MHD); Compound 745 is a liquid medicine containing pH 4.75 containing 10 mM sodium acetate, 9% (w/v) sucrose, and 0.004% (w/v) polysorbate 20. In the form of a composition; the compound 745 is administered intravenously once a dose of 1 mg/kg to 10 mg/kg, and may be administered once a week at the initial dose for a first period of time, followed by a second dose at a maintenance dose. The initial dose is greater than the maintenance dose during the time period; and the method results in a statistically significant increase in LBM as determined by dual energy X-ray absorptiometry (DXA). A compound 745 for use in the treatment of PEW in ESRD patients undergoing MHD. A use of Compound 745 for the treatment of PEW in ESRD patients undergoing MHD. Use of a compound 745 for the manufacture of a medicament for the treatment of PEW in an ESRD patient undergoing MHD. A method of making an agent intended to treat PEW in an ESRD patient undergoing MHD, wherein Compound 745 is used.