Methods and compositions for treating chronic lung disease

Abstract

To provide methods for treating Chronic Lung Disease (CLD).SOLUTION: A method comprises administering insulin-like growth factor-1 (IGF-1) or an agonist or analog thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference to related application The present application claims priority to U.S. Provisional Patent Application No. 62 / 557,113 filed on September 11, 2017, and the disclosure of said provisional application is incorporated herein by reference in its entirety. Background Art

[0002] Background Every year, an estimated 4.2 million children are born in the United States, of which about 383,000 (about 9%) are born prematurely. Preterm labor and its complications are major perinatal public health issues in today's developed countries. Infants born prematurely with low birth weight lose most of an important period of intrauterine development. These account for half of all infant deaths and three-quarters of long-term morbidity. Special care and the high costs associated therewith impose a heavy burden on the national finances throughout the neonatal period and the lifetime of survivors. Many survivors also have a reduced quality of life due to physical damage directly caused by prematurity.

[0003] Normal pregnancy and conception are considered to last 40 weeks (280 days) from the date of conception. Infants born before 37 weeks of gestation are considered premature and may be at risk of complications. Advances in medical technology have made it possible for infants born as early as 23 weeks (17 weeks premature) to survive. Infants born prematurely are at high risk of death or serious complications due to low birth weight and immature bodily systems. Low birth weight is defined with a 2,500g cutoff and serves as a marker for high-risk newborns. Low birth weight is correlated with prenatal risk factors, complications during labor, and neonatal disease and accounts for a large proportion of preterm births. Research on very low birth weight has defined cutoffs of less than 1,500g or less than 1,000g, which identify high-risk infants with a high rate of severe respiratory and neurological complications associated with extreme prematurity. (See Hack, M., Klein, NK, & Taylor, HG, Long-term developmental outcomes of low birth weight infants. The Future of Children, 5, 176-196 (1995) (Non-patent document 1)).

[0004] The lungs, digestive tract, and nervous system (including the brain) are not fully developed in premature infants and are particularly vulnerable to complications. The most common medical problems faced by premature infants are retinopathy of prematurity, growth retardation, intellectual disability, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, and intraventricular hemorrhage.

[0005] Chronic lung disease (CLD) is a particularly challenging and life-threatening condition in premature infants. Premature infants, especially extremely premature infants, are at very high risk of developing chronic lung disease, particularly bronchopulmonary dysplasia (BPD), during the early manifestation period. The long-term trajectory of lung outcomes in infants born extremely prematurely typically begins with prenatal risk factors, followed by respiratory distress syndrome (RDS) requiring respiratory support for the first hour or days after birth, a diagnosis of BPD in patients who survive to term equivalence, and ultimately, chronic respiratory morbidity during infancy, early childhood, and often into school age or adolescence. Chronic respiratory morbidity frequently leads to respiratory-related readmissions and emergency room visits, requires respiratory medication or home respiratory support, and often results in airway hyperresponsiveness, limiting quality of life. The majority of infants with biparietal disease (BPD) at 36 weeks develop persistent lung disease at corrected age of 12-24 months, but some infants develop chronic lung disease later in infancy even if they are not diagnosed with BPD. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hack, M., Klein, NK, & Taylor, HG, Long-term developmental outcomes of low birth weight infants. The Future of Children, 5, 176-196 (1995) [Overview of the project]

[0007] overview This invention provides an effective treatment for chronic lung disease (CLD) in premature infants. This invention is partly based on the finding that the combined use of IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3) improves not only short-term outcomes but also long-term conditions for chronic lung disease, thereby significantly improving the growth and developmental arch of infants born in an extremely premature state, which begins immediately after birth when the supply of IGF-1 from the mother is interrupted and continues until it is replenished.

[0008] In one embodiment of the present disclosure, a method for treating chronic lung disease (CLD) is provided, the method comprising administering insulin-like growth factor-1 (IGF-1) or its agonist or analog to a subject in need of treatment. In some embodiments, a method for treating CLD is provided, the method comprising administering a composition comprising IGF-I or its agonist or analog, comprising IGF-1 and an IGF-binding protein, to a subject in need of treatment. In some embodiments, the combination comprises IGF-I or its agonist or analog, and further comprises IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3).

[0009] In some embodiments, the subject requiring treatment is an infant. In some embodiments, the subject is a premature infant, where the infant was born at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 2 months, at least 10 weeks, or at least 3 months premature.

[0010] In some embodiments, subjects in need of treatment are administered a composition comprising IGF-I or its agonist or analog, which is administered subcutaneously, intravenously, intramuscularly, or orally. In some embodiments, IGF-I or its agonist or analog is administered intravenously. In some embodiments, IGF-I or its agonist or analog is administered at a dose of approximately 100 to 500 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of 100 to 450 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of 150 to 400 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of 200 to 400 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of 250 micrograms / kg / 24 hours to 400 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of approximately 250 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of approximately 400 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered from birth until postmenstrual age (PMA), which is approximately 24 to 34 weeks. PMA is defined as the infant's age in weeks at the time of discharge from the hospital, death, or the first birthday, whichever comes first. PMA is calculated as the sum of (i) total gestational weeks multiplied by 7, (ii) days of gestation, and (iii) days of hospitalization after birth. In some embodiments, IGF-I or its agonist or analog is administered from birth until approximately 28-32 weeks (PMA). In some embodiments, IGF-I or its agonist or analog is administered from birth until approximately 29 weeks and 6 days (PMA).

[0011] In some embodiments of this disclosure, the subject has a reduced serum IGF-1 level. In some embodiments, the reduced serum IGF-1 level is less than 60 micrograms / L. In some embodiments, the reduced serum IGF-1 level is less than 50 micrograms / L. In some embodiments, the reduced serum IGF-1 level is less than 40 micrograms / L. In some embodiments, the reduced serum IGF-1 level is approximately 30 to 50 micrograms / L.

[0012] In some embodiments, IGF-1 is recombinantly synthesized. In some embodiments, IGFBP-3 is recombinantly synthesized. In some embodiments, IGF-1 and IGFBP-3 are complexed before administration to the subject. In some embodiments, IGF-1 and IGFBP-3 are complexed in equimolar amounts.

[0013] The methods provided herein include embodiments in which administration of IGF-I or its agonist or analog results in a reduction in the incidence of chronic respiratory disease (CRM) up to a corrected age (CA) of 12 months. The corrected age of an infant is the infant's age adjusted based on the expected date of delivery. Considering that the gestation period is 40 weeks (i.e., the expected date of delivery), the corrected age of a premature infant is the actual age minus the extra time spent outside the womb. In some embodiments, administration of IGF-I or its agonist or analog results in a reduction in the incidence of bronchopulmonary dysplasia (BPD) up to a postmenstrual age (PMA) of 24 weeks to 12 months. For example, administration of IGF-I or its agonist or analog results in a reduction in the incidence of BPD up to a PMA of 24 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, or 38 weeks, or 40 weeks, 45 weeks, 50 weeks, or 52 weeks. In some other embodiments, administration of IGF-I or its agonist or analog results in a reduced incidence of bipolar disorder (BPD) up to 6 months, 8 months, 10 months, or 12 months postmenstrual age (PMA). In some embodiments, administration of IGF-I or its agonist or analog results in a reduced incidence of severe intraventricular hemorrhage (IVH) grade III or IV up to 24 weeks, 30 weeks, 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months postmenstrual age (PMA). In some embodiments, administration of IGF-I or its agonist or analog results in a reduced incidence of retinopathy of prematurity (ROP) up to 24 weeks, 30 weeks, 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months postmenstrual age (PMA).

[0014] The methods disclosed herein include embodiments in which administration of IGF-I or its agonist or analog results in an improvement in functional status as assessed by the Premature Infant Index (PREMII) up to postmenstrual age (PMA) of 24 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 50 weeks, 6 months, 8 months, 10 months, or 12 months.

[0015] [Invention 1001] A method for treating chronic lung disease, comprising administering insulin-like growth factor-1 (IGF-1) or its agonist or analog to a patient in need of treatment. [Invention 1002] The method of the present invention 1001, wherein the IGF-I or its agonist or analog comprises IGF-1 and an IGF-binding protein. [Invention 1003] The method of the present invention 1002, wherein the IGF-I or its agonist or analog comprises IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3). [Invention 1004] Any method of the present invention, wherein the subject requiring treatment is an infant. [Invention 1005] The method of the present invention, wherein the subject is a premature infant. [Invention 1006] The method of the present invention 1005, wherein the infant was born at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, or at least three months early. [Invention 1007] The method of the present invention wherein the IGF-I or its agonist or analog is administered subcutaneously, intravenously, intramuscularly, or orally. [Invention 1008] The method of the present invention 1007, wherein the IGF-I or its agonist or analog is administered intravenously. [Invention 1009] The method of the present invention 1008, wherein the IGF-I or its agonist or analog is administered at a dose of approximately 100 to 500 micrograms / kg / 24 hours. [Invention 1010] The method of the present invention 1008, wherein the IGF-I or its agonist or analog is administered at a dose of approximately 250 micrograms / kg / 24 hours. [Invention 1011] The method of the present invention 1008, wherein said IGF-I or an agonist or analog thereof is administered at a dose of about 400 micrograms / kg / 24 hours. [Invention 1012] The method according to any of the foregoing aspects of the present invention, wherein said IGF-I or an agonist or analog thereof is administered from birth to a postmenstrual age (PMA) of about 24 to 34 weeks. [Invention 1013] The method according to any of the foregoing aspects of the present invention, wherein said IGF-I or an agonist or analog thereof is administered from birth to a PMA of about 28 to 32 weeks. [Invention 1014] The method according to any of the foregoing aspects of the present invention, wherein said IGF-I or an agonist or analog thereof is administered from birth to a PMA of 29 weeks and 6 days. [Invention 1015] The method according to any of the foregoing aspects of the present invention, wherein said subject has reduced serum IGF-1 levels. [Invention 1016] The method of the present invention 1015, wherein said reduced serum IGF-1 level is about 30 to 50 micrograms / L. [Invention 1017] The method according to any of the foregoing aspects of the present invention, wherein said IGF-1 is produced recombinantly. [Invention 1018] The method according to any one of the present inventions 1003 to 1017, wherein said IGFBP-3 is produced recombinantly. [Invention 1019] The method according to any one of the present inventions 1003 to 1018, wherein said IGF-1 and said IGFBP-3 are complexed prior to administration to said subject. [Invention 1020] The method of the present invention 1019, wherein said IGF-1 and IGFBP-3 are complexed in equimolar amounts. [Invention 1021] The method according to any of the foregoing aspects of the present invention, wherein administration of said IGF-I or an agonist or analog thereof results in reduced incidence of Chronic Respiratory Morbidity (CRM) up to a corrected age (CA) of 12 months. [Invention 1022] Any method of the present invention wherein administration of IGF-I or its agonist or analog results in a reduction in the incidence of bronchopulmonary dysplasia (BPD) up to postmenstrual age (PMA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months. [Invention 1023] Any method of the present invention wherein administration of IGF-I or its agonist or analog results in a reduction in the incidence of severe intraventricular hemorrhage (IVH) grade III or IV up to postmenstrual age (PMA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months. [Invention 1024] Any method of the present invention wherein administration of IGF-I or its agonist or analog results in a reduction in the incidence of retinopathy of prematurity (ROP) up to postmenstrual age (PMA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months. [Invention 1025] Any method of the present invention wherein the administration of IGF-I or its agonist or analog results in an improvement in functional status as assessed by the Premature Infant Index (PREMII) up to postmenstrual age (PMA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months. Although the present invention is described in conjunction with preferred specific embodiments, it should be understood that the foregoing and the following embodiments are intended to illustrate the scope of the invention and are not intended to limit it. Other aspects, advantages and modifications within the scope of the invention will be obvious to those skilled in the art to which the invention pertains. [Modes for carrying out the invention]

[0016] Detailed explanation The present invention provides methods and compositions for treating chronic lung disease. The compositions and methods provided herein are particularly effective for treating chronic lung disease in premature infants, especially extremely premature infants. In some embodiments, the methods of the present invention include administering insulin-like growth factor-1 (IGF-1) or its agonist or analog to a subject in need of treatment (e.g., a premature infant). In some embodiments, IGF-1 or its agonist or analog comprises IGF-1 and an IGF-binding protein (e.g., insulin-like growth factor-binding protein-3 (IGFBP-3)).

[0017] Various aspects of the present invention are described in detail in the following sections. The use of these sections is not intended to limit the present invention. Each section may be applied to any aspect of the present invention. In this application, the use of "or" means "and / or" unless otherwise stated.

[0018] definition "Preterm," "premature," "immature," "premature infant," or "premature newborn," or their grammatical equivalents, refer to a patient being born before 40 weeks of gestation or being 10% below the average birth weight for the patient's gestational age. In some embodiments, premature refers to an infant born at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, or at least three months premature.

[0019] "IGF-I" refers to insulin-like growth factor I derived from any species, preferably including cattle, sheep, pigs, horses, and humans, and if referring to exogenous administration, it refers to insulin-like growth factor I derived from any species, whether natural, synthetic, or recombinant, provided that it binds to an IGF-binding protein at an appropriate site. IGF-I can be produced by recombinant means, for example, as described in PCT Publication WO95 / 04076.

[0020] "IGFBP" or "IGF-binding protein" refers to a protein or polypeptide derived from the insulin-like growth factor-binding protein family that typically associates with, binds to, or complexes with IGF-I, whether circulating or not (i.e., in serum or tissue). This binding protein does not contain a receptor. This definition includes IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, IGFBP-6, Mac 25 (IGFBP-7), and prostacyclin-stimulating factor (PSF), or endothelial cell-specific molecule (ESM-1), as well as other proteins with high homology to IGFBPs. Mac25 is described, for example, in Swisshelm et al., Proc. Natl. Acad. Sci. USA, 92:4472-4476 (1995) and Oh et al., J. Biol. Chem., 271:30322-30325 (1996). PSF is described in Yamauchi et al., Biochemical Journal, 303:591-598 (1994). ESM-1 is described in Lassalle et al., J. Biol. Chem., 271:20458-20464 (1996).For other identified IGFBPs, see, for example, EP 375,438 published June 27, 1990; EP 369,943 published May 23, 1990; WO89 / 09268 published October 5, 1989; Wood et al., Molecular Endocrinology, 2:1176-1185 (1988); Brinkman et al., The EMBO J., 7:2417-2423 (1988); Lee et al., Mol. Endocrinol., 2:404-411 (1988); Brewer et al., BBRC, 152:1289-1297 (1988); EP 294,021 published December 7, 1988; Baxter et al. See also al., BBRC, 147:408-415 (1987); Leung et al., Nature, 330:537-543 (1987); Martin et al., J. Biol. Chem., 261:8754-8760 (1986); Baxter et al., Comp. Biochem. Physiol., 91B:229-235 (1988); WO 89 / 08667 published September 21, 1989, WO 89 / 09792 published October 19, 1989, and Binkert et al., EMBO J., 8:2497-2502 (1989).

[0021] "IGFBP-3" refers to insulin-like growth factor binding protein 3. IGFBP-3 is a member of the insulin-like growth factor binding protein family. IGFBP-3 may originate from any species, including cattle, sheep, pigs, and humans, and may be in its natural sequence or variant form, but is not limited to variants of the natural allele. IGFBP-3 may originate from any source, whether natural, synthetic, or recombinant, provided that it binds to IGF-I at an appropriate site. IGFBP-3 can be synthesized by recombinant DNA, as described in PCT Publication WO95 / 04076.

[0022] As used herein, “therapeutic composition” is defined as a composition comprising IGF-I, its analogues, or IGF-I combined with its binding protein, IGFBP-3 (an IGF-I / IGFBP-3 complex). The therapeutic composition may also contain other substances, such as water, minerals, carriers such as proteins, and other excipients known to those skilled in the art.

[0023] An IGF-I "analog" is a compound that has the same therapeutic effect as IGF-I in humans or animals. These may be a naturally occurring analog of IGF-I (e.g., cleaved IGF-I) or any of the known synthetic analogs of IGF-I. For example, see U.S. Patent No. 5,473,054 regarding IGF-I analog compounds.

[0024] IGF-I "agonists" are peptide-containing compounds that can increase serum and tissue levels of IGF, particularly IGF-I, in mammals, especially humans. For more information on IGF agonist molecules, see, for example, U.S. Patent No. 6,251,865.

[0025] As used herein, “developmental delay” means abnormal neurogenesis that may lead to a delay in mental progress in achieving developmental milestones. In some cases, developmental delay may be determined by electroencephalography.

[0026] As used herein, “Subject” means any mammal, including humans. In certain embodiments of the present invention, the subject is an adult, adolescent, or minor. The present invention aims to provide a method for administering a pharmaceutical composition and / or administering it in utero.

[0027] As used herein, the term “treatment” (“to treat” or “to treat”) means the administration of any therapeutic composition (e.g., IGF-1 or its agonist or analog) that partially or completely reduces, improves, alleviates, inhibits, delays the onset, prevents, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition (e.g., chronic lung disease). Such treatment may be for subjects who show no signs of the disease, disorder, and / or condition in question, as well as for subjects who show only initial signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be for subjects who show one or more established signs of the disease, disorder, and / or condition in question.

[0028] As used herein, the terms “improve,” “increase,” or “decrease,” or their grammatical equivalents, refer to values ​​compared to, for example, measurements in the same individual before the initiation of the treatment described herein, or measurements in a control individual (or more control individuals) not receiving the treatment described herein, or to a reference measurement such as medical history reference or data. A “control individual” is an individual with the same type of chronic lung disease as the individual being treated, and is approximately the same age as the individual being treated (to ensure that the disease stages in the treated individual and the control individual are comparable).

[0029] chronic lung disease The present invention may be used to treat any type of chronic lung disease (CLD) occurring in adults, particularly the elderly, and infants, particularly premature or extremely premature infants. CLD includes, but is not limited to, a diverse range of diseases and disorders, including COPD (emphysema and chronic bronchitis), asthma, cystic fibrosis, restrictive lung disease, and persistent infections.

[0030] Chronic lung disease in premature infants Extremely premature infants are at a very high risk of developing chronic lung disease. Premature babies may require a ventilator (mechanical ventilation) and additional oxygen to breathe. Chronic lung disease occurs when the ventilator or oxygen damages the lungs of a premature baby. Lung damage causes inflammation of the inner tissue of the newborn's lungs. The tissue is destroyed, and scarring occurs. Scarring causes respiratory distress, and the newborn may require more oxygen. Lung damage can occur by: • Prematurity: The lungs of premature infants are not fully formed. This is especially true of the alveoli. • Small amounts of surfactant: This is a substance in the lungs that helps keep the small alveoli open. • Oxygen use: Excessive oxygen can damage cells in the lungs. • Respiratory equipment (mechanical ventilation): Air pressure can damage the lungs. This pressure can be created by the use of ventilators, airway suctioning, and endotracheal (ET) tubes. An ET tube is placed in the neonatal trachea (windpipe / trachea) and connected to a ventilator.

[0031] Regarding the lung outcomes of infants born extremely prematurely, the long-term trajectory typically begins with prenatal risk factors, followed by respiratory distress syndrome requiring respiratory support for the first hour or days after birth. Patients who survive to full term are diagnosed with bipolar disorder (BPD), and ultimately develop a chronic respiratory condition during infancy, early childhood, and often into school age or adolescence. This chronic respiratory condition frequently leads to respiratory-related readmissions and emergency room visits, requires respiratory medication or home respiratory support, and often results in airway hyperresponsiveness, limiting quality of life.

[0032] IGF-1 or its agonist or analog The present invention can be carried out using IGF-1 or its agonist or analog. IGF-I is a known postnatal growth and metabolic regulator. See Baker J, Liu JP, Robertson EJ, Efstratiadis A. It has a molecular weight of approximately 7.5 kilodaltons (Kd). Most circulating IGF binds to IGF-binding proteins, particularly IGFBP-3. IGF-I can be measured in serum to diagnose conditions associated with abnormal growth.

[0033] Typically, a therapeutic composition suitable for treating CLD according to the present invention contains IGF-1 and an IGF-1 binding protein, such as IGF-binding protein (IGFBP). At least six distinct IGF-binding proteins (IGFBPs) have been identified in various tissues and body fluids. In some embodiments, a suitable therapeutic composition according to the present invention contains IGF-1 and IGFBP-3. IGF-1 and IGFBP-3 may be used as a protein complex or separately.

[0034] IGF-I and IGFBP-3, which are IGF-I binding proteins, may be purified from natural sources or produced by recombinant methods. For example, the purification of IGF-I from human serum is known in this field (Rinderknecht et al. (1976) Proc.Natl.Acad.Sci.USA 73:2365-2369). The preparation of IGF-I by recombinant methods is described in EP0128-733, published in December 1984. IGFBP-3 may be purified from natural sources using methods such as those described by Baxter et al. (1986, Biochem.Biophys.Res.Comm.139:1256-1261). Alternatively, IGFBP-3 may be recombinantly synthesized as described in Sommer et al., pp. 715-728, Modern Concepts Of Insulin-Like Growth Factors (EMSpencer, ed., Elsevier, NY, 1991). Recombinant IGFBP-3 binds to IGF-I in a 1:1 molar ratio.

[0035] Pharmaceutical compositions and therapeutic uses The present invention provides compositions and methods for treating patients with chronic lung disease (CLD), particularly CLD associated with prematurity. For example, the present invention may be used to treat premature infants with CLD or CLD-related complications. In some embodiments, the present invention may be used to treat infants born at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, or at least three months premature. In some embodiments, the present invention may be used to treat extremely premature infants.

[0036] In one embodiment of the present invention, IGF-I or an analog thereof is administered in combination with an IGF-binding protein capable of binding to IGF-I. In some embodiments, the IGF-binding protein capable of binding to IGF-I is IGF-binding protein 3 (IGFBP-3).

[0037] A composition containing equimolar amounts of IGF-I and IGF-binding protein may be used. In some embodiments, IGF-I and IGF-binding protein are complexed before administration. This complex may be formed by mixing approximately equimolar amounts of IGF-I and IGF-binding protein dissolved in a physiologically compatible carrier, such as saline or phosphate-buffered saline. In some embodiments, a concentrated solution of recombinant human IGF-I and a concentrated solution of recombinant human IGF-binding protein are mixed together for a sufficient time for an equimolar complex to form. In some embodiments, as described in International Patent Application No. WO96 / 40736, recombinant human IGF-I and recombinant human IGF-binding protein are combined to form a complex during purification.

[0038] For therapeutic use, IGF-I or its analogs may be administered to the patient either alone or as part of a pharmaceutical composition, which comprises IGF-I or its analogs together with one or more acceptable carriers and optionally other therapeutic components. The carriers must be "acceptable" in the sense that they are compatible with the other components of the formulation and are not harmful to the patient.

[0039] Examples of pharmaceutical compositions of the present invention include those suitable for oral administration, nasal administration, topical administration (including oral and sublingual administration), or parenteral administration (including subcutaneous, intramuscular, intravenous, and intradermal administration). The formulations may be in convenient unit dosage forms such as tablets and sustained-release capsules, or liposomes, and may be prepared by any method known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (17th ed. 1985).

[0040] Such preparation methods include a step of associating the administered molecule with a carrier, such as one or more accessory components. Generally, compositions are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, liposomes, or finely divided solid carrier, or all of these, and then shaping the product if necessary.

[0041] The compositions of the present invention suitable for oral administration may be in the form of separate units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, as an oil-in-water or water-in-oil emulsion, encapsulated in liposomes, or as a bolus.

[0042] Tablets may be prepared by compression or molding with one or more accessory components as optional. Compressed tablets may be prepared by compressing a free-flow active ingredient, such as a powder or granules, with optionally a binder, lubricant, inert diluent, preservative, surface activator, or dispersant in appropriate equipment. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in appropriate equipment. Tablets may optionally be coated or marked, and may be formulated so that the active ingredient contained therein is released slowly or its release is controlled.

[0043] Compositions suitable for parenteral administration include aqueous or non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that provide isotonicity with the intended recipient's blood. Also included are aqueous or non-aqueous sterile suspensions, which may contain suspending agents and thickeners. The formulations may be in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze-dried / lyophilized conditions requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Injectable solutions and suspensions for immediate preparation may be prepared from sterile powders, granules, and tablets.

[0044] The methods of the present invention disclosed herein provide methods for parenteral and oral administration of IGF-I, its analogues or agonists, or IGF-I or analogues used in combination with IGF-binding protein complexes, to infants requiring such treatment. Parenteral administration includes, but is not limited to, intravenous (IV), intramuscular (IM), subcutaneous (SC), intraperitoneal (IP), intranasal, and inhalation routes. In the methods of the present invention, IGF-I, its agonist or analogues are preferably administered orally. IV, IM, SC, and IP administrations may be by bolus or infusion, and may also be by sustained-release implantable devices, including, but not limited to, pumps, sustained-release formulations, and mechanical devices. The formulation, route of administration, method of administration, and dosage will depend on the disorder being treated and the patient's medical history. In some embodiments, IGF-I or its agonist or analogues are administered intravenously.

[0045] The pharmaceutical composition according to the present invention can be administered in various doses. For example, a suitable dose may be in the range of about 100 to 500 micrograms / kg / 24 hours. In some embodiments, a suitable dose may be about 100 micrograms / kg / 24 hours, 150 micrograms / kg / 24 hours, 200 micrograms / kg / 24 hours, 250 micrograms / kg / 24 hours, 300 micrograms / kg / 24 hours, 350 micrograms / kg / 24 hours, 400 micrograms / kg / 24 hours, 450 micrograms / kg / 24 hours, or 500 micrograms / kg / 24 hours, or higher. In some embodiments, the pharmaceutical composition according to the present invention is administered from birth to about 24 to 34 weeks postmenstrual age (PMA), to about 28 to 32 weeks PMA, or to about 29 weeks + 6 days PMA.

[0046] The methods provided herein include embodiments in which administration of IGF-I or its agonist or analog results in a reduction in the incidence of chronic respiratory disease (CRM) up to 12 months of corrected age (CA). In some embodiments, administration of IGF-I or its agonist or analog results in a reduction in the incidence of bronchopulmonary dysplasia (BPD) up to 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months of postmenstrual age (PMA). In some embodiments, administration of IGF-I or its agonist or analog results in a reduction in the incidence of severe intraventricular hemorrhage (IVH) grade III or IV up to 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months of postmenstrual age (PMA). In some embodiments, administration of IGF-I or its agonist or analog reduces the incidence of retinopathy of prematurity (ROP) up to postmenstrual age (PMA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months.

[0047] The methods disclosed herein include embodiments in which administration of IGF-I or its agonist or analog results in an improvement in functional status as assessed by the Premature Infant Index (PREMII) up to postmenstrual age (PMA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months.

[0048] With regard to parenteral or oral administration, the complex composition may be a semi-solid or liquid preparation, such as a liquid or suspension. A physiologically compatible carrier is one that is non-toxic to the recipient at the dose and concentration used and compatible with the other components of the formulation. For example, the formulation preferably does not contain oxidizing agents and other compounds known to be harmful to polypeptides. Therefore, physiologically compatible carriers are not limited to, but include physiological saline, serum albumin, 5% dextrose, plasma preparations, and other protein-containing solutions. Optionally, detergents or surfactants may also be used as carriers.

[0049] In yet another aspect of the present invention, the use of IGF-I, its agonist, or an analog is provided in the manufacture of a therapeutic composition for treating complications of premature birth.

[0050] Finally, a product comprising packaging material and a drug contained within the packaging material is also provided. The packaging material includes a label indicating that the drug may be administered in an effective dose for a sufficient period of time to treat and / or prevent complications associated with premature birth. The drug comprises IGF-I, its agonist or analog, along with a pharmaceutically acceptable carrier.

[0051] The present invention will be further illustrated by the following examples intended to illustrate the present invention. [Examples]

[0052] Example 1. Treatment of CLD in extremely premature infants This study investigated the efficacy of an investigational drug containing an insulin-like growth factor-1 / insulin-like growth factor-binding protein-3 (rhIGF-1 / rhIGFBP-3) complex in the treatment of chronic lung disease (CLD). This was a multicenter, randomized, open-label, three-arm study designed to evaluate the clinical efficacy and safety of a therapeutic composition in the prevention of human chronic lung disease. The study included subjects up to 12 months of corrected age (CA) and was compared to standard neonatal care for extremely premature infants. This study was reviewed and approved by the responsible institutional ethics board (IRB) / healthcare ethics committee (IEC).

[0053] the purpose: The purpose of this study is to determine whether the investigational drug containing rhIGF-1 / rhIGFBP-3 (hereinafter referred to as the therapeutic composition) can reduce respiratory complications in extremely premature infants up to 12 months of corrected age (CA), compared to extremely premature infants who received only standard neonatal care.

[0054] Subjects The study includes participants with a gestational age (GA) of 23 weeks + 0 days to 27 weeks + 6 days. Both males and females are included. At least 50 participants are included in this study.

[0055] Exclusion criteriaExclusion criteria include, in accordance with the opinion of the principal investigator, detectable macroscopic congenital abnormalities, identified or suspected chromosomal abnormalities, hereditary disorders or syndromes. Exclusion criteria also include sustained blood glucose levels of less than 2.5 mmol / L per liter at reference visit to exclude severe congenital abnormalities of glucose metabolism; clinically significant neurological disorders in the opinion of the principal investigator; monozygotic multiples; and any other conditions that may pose a risk to the subject, interfere with the subject's ability to adhere to the protocol, or interfere with the interpretation of results. A subject will be excluded if they are participating in or are scheduled to participate in a clinical trial of another investigational drug, investigational device, or investigational method (participation in observational studies is permitted on a case-by-case basis). A subject will also be excluded if they, their parents, or legally authorized representatives are unable to adhere to the protocol or are unlikely to be able to attend the long-term follow-up period determined by the principal investigator.

[0056] Test design details The primary objective of this study is the prevention of bronchopulmonary dysplasia and chronic lung disease. This is an open-label study, and the intervention model is a parallel-group comparison study. The conditions monitored are BPD and CLD.

[0057] A therapeutic composition of 250 micrograms / kg / 24 hours will be administered intravenously (IV) to one group of subjects (Group A) from birth until 29 weeks and 6 days postmenstrual age (PMA). Another group of subjects (Group B) will receive a therapeutic composition of 400 micrograms / kg / 24 hours intravenously (IV) from birth until 29 weeks and 6 days postmenstrual age (PMA). A third group (Group C or control group) will receive only standard neonatal care.

[0058] The primary outcome measured is the incidence of chronic respiratory disease (CRM) up to 12 months of corrected age (CA) [timeframe: from baseline to 12 months of corrected age (CA)]. CRM is a common adverse outcome in premature infants, resulting in recurrent respiratory symptoms requiring treatment with pulmonary medications such as bronchodilators, and particularly during the first year of life, requiring home oxygen support, frequent emergency room visits, or readmissions. CRM is measured by the use of respiratory care and respiratory symptoms.

[0059] Secondary outcomes include the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA) [timeframe: 36 weeks PMA]. BPD is a chronic lung disorder characterized by pulmonary immaturity, undifferentiated alveoli and pulmonary diastolic dysfunction with the presence of hyaline membranes, dilated capillaries immersed in the mesenchymal tissue, and distorted deposition of the extracellular matrix. BPD has persistent effects on lung function and is associated with subsequent neurodevelopmental problems in childhood.

[0060] The following are also listed as secondary outcomes. • Incidence of severe intraventricular hemorrhage (IVH) of grade III or IV up to 40 weeks postmenstrual age (PMA) [Time frame: from baseline to 40 weeks PMA]. • Incidence of bronchopulmonary dysplasia (BPD) at 40 weeks postmenstrual age (PMA) [Time frame: 40 weeks PMA]. • Incidence of chronic respiratory disease (CRM) or death up to 6 months corrected age (CA) [time frame: from baseline to 6 months corrected age (CA)]. CRM is a common adverse outcome in premature infants, resulting in recurrent respiratory symptoms requiring treatment with pulmonary medications such as bronchodilators, and particularly during the first year of life, requiring home oxygen support, frequent emergency room visits, or readmissions. CRM is measured by the use of respiratory care and respiratory symptoms. • Functional status as assessed by the Prematurity Index (PREMII) at 40 weeks postmenstrual age (PMA) [Time frame: 36 weeks PMA]. PREMII is a Clinician-Reported Outcome (ClinRO) assessment used to capture the overall functional maturity of extremely premature infants. Functional status is defined as what the infant is able to do in eight key functional areas (feeding, weight gain, thermoregulation, respiratory support, apnea, bradycardia, hyposaturation events, and oxygen administration) as a reflection of the infant's overall health and development.

[0061] Example 2. Prevention of BPD in extremely premature infants A randomized trial investigating the effects of IGF-1 / IGFBP3 in BPD prevention was conducted using a parallel-group intervention model. This trial was conducted at multiple sites in Italy, the Netherlands, Poland, Sweden, the United Kingdom, and the United States from June 18, 2010 to March 30, 2016.

[0062] Mecasermin Rinfabate, an IGF-1 / IGFBP3 drug, was administered to subjects as a continuous intravenous infusion from day 0 (birthday) until 29 weeks + 6 days post-majority (PMA), when the subjects' endogenous IGF-1 production was deemed sufficient to maintain physiological serum IGF-1 levels. After discontinuation of the investigational drug infusion, each subject was followed up until 40 weeks ± 4 days post-majority (PMA). The purpose of this study was to determine the dose of rhIGF-1 / rhIGFBP-3 administered as a continuous intravenous infusion (CI) necessary to establish and maintain long-term serum IGF-1 levels within physiological ranges in prematurity infants in order to prevent retinopathy of prematurity. This study was a phase II randomized, controlled, evaluator-blinded, dose-confirming, pharmacokinetic, safety, and efficacy study of rhIGF-1 / rhIGFBP-3. Sixty-one subjects received insulin-like growth factor (rhIGF-I) / insulin-like growth factor-binding protein-3 (rhIGFBP-3) via continuous intravenous (IV) infusion at a rate of 250 micrograms per kilogram (mcg / kg) over 24 hours, from day 0 to 29 weeks and 6 days postmenstrual age (PMA). Sixty subjects served as a control group, receiving only standard treatment. Table 1 shows the overall study flow for the subjects.

[0063] (Table 1) Participant flow: Overall study TIFF0007923863000001.tif67160

[0064] Table 2 shows the population for this test.

[0065] (Table 2) TIFF0007923863000002.tif79170

[0066] The secondary outcomes during the ongoing study included the following parameters in particular: • Time from neonatal intensive care (TDNIC) to discharge [Time frame: Day 0 to 40 weeks postmenstrual age (EOS)]. • Number of subjects with bronchopulmonary dysplasia (BPD) [Time frame: 36 weeks postmenstrual]. The severity of BPD, categorized as mild, moderate, and severe, is based on the National Institute of Child Health and Human Development (NICHD) guidelines for premature infants born at less than 32 weeks of gestation (GA). • Mild: Oxygen is required for the first 28 days, but the patient will be able to breathe room air by 36 weeks postpartum mastitis (PMA) or upon discharge and returning home, whichever comes first. • Moderate BPD: Requires oxygen for the first 28 days, but requires less than 30 percent oxygen by 36 weeks postpartum mastopaedication (PMA) or discharge and return home, whichever comes first. • Severe BPD: Requires oxygen for the first 28 days and requires (≥)30% oxygen via a head hood or nasal cannula, continuous positive airway pressure, mechanical ventilation, or high-flow nasal cannula of ≥2 L / min at PMA 36 weeks or discharge and home, whichever comes first. • Weight change rate [Time frame: Day 0 to 40 weeks postmenstrual age (EOS)]. The rate of change is the specific weight change in kilograms (kg) per day. • Percentage change in height [Time frame: Day 0 to 40 weeks postmenstrual (EOS)]. • The rate of change is the change in height in centimeters (cm) per day. Number of subjects with treatment-induced adverse events (TEAEs) and treatment-induced serious adverse events (TESAEs) [time frame: Day 0 to 40 weeks postmenstrual age (EOS)]. Adverse events (AEs) were defined as any adverse medical event in a subject administered the investigational drug, regardless of the possibility of causal relationship. Serious adverse events (SAEs) were defined as any AE that leads to any of the following outcomes, or any AE that is considered serious for any other reason: death; initial hospitalization or prolonged hospitalization of a patient; life-threatening event (imminent risk of death); persistent or significant physical disability / incapacity; birth defects. Adverse events occurring under treatment were defined as the occurrence of an AE on the day of the first administration of the test product, or any subsequent AE, or an exacerbation of the severity of a pre-existing AE. • Percentage of serum IGF-1 concentrations within the target range after rhIGF-1 / rhIGFBP-3 infusion [Time frame: Day 0 to 40 weeks postmenstrual (EOS)]. Serum samples were collected from both treatment and control subjects, and IGF-1 levels were quantified using certified immunoassay methods. The target range for serum IGF-1 was 28–109 mcg / L. The percentage of treatment subjects whose serum IGF-1 levels fell within this range was reported. • Serum concentration of IGFBP-3 after intravenous (IV) infusion of rhIGF-1 / rhIGFBP-3 [Time frame: Day 0 to 40 weeks postmenstrual]. • Serum concentrations of acid-unstable subunits (ALS) after intravenous (IV) infusion of rhIGF-1 / rhIGFBP-3 [Time frame: Day 7 to 40 weeks postmenstrual].

[0067] Table 3 shows the BPD values ​​measured as a secondary outcome.

[0068] (Table 3) TIFF0007923863000003.tif84160

[0069] Statistical analysis regarding the number of subjects with bronchopulmonary dysplasia (BPD) was not presented.

[0070] While the specific compounds, compositions, and methods described herein are described in a particular manner according to specific embodiments, the following examples are for illustrative purposes only and are not intended to limit the compounds of the present invention.

[0071] The articles “a” and “an” as used herein and in the claims should be understood to include multiple referents unless explicitly indicated otherwise. Claims or descriptions containing “or” between one or more members of a group are considered satisfied if one, two or more, or all of the group members are present in, employed in, or otherwise related to a given product or process, unless the context indicates otherwise or otherwise. The present invention includes embodiments in which just one member of a group is present in, used in, or related to a given product or process. The present invention also includes embodiments in which two or more, or all, group members are present in, used in, or related to a given product or process. Furthermore, unless otherwise indicated or unless it is obvious to a person skilled in the art that this invention includes all variations, combinations, and substitutions of one or more limitations, elements, phrases, descriptive terms, etc., from one or more of the enumerated claims introduced into another claim dependent on the same basic claim (or other related claim), unless otherwise indicated or unless it would be obvious to a person skilled in the art that this would result in a contradiction or inconsistency. Where elements are presented as a list (e.g., a Markush group or similar format), each subgroup of the elements is also disclosed, and it should be understood that any element may be removed from a group. In general, the present invention or aspects of the present invention are referred to as including certain elements, features, etc., and it should be understood that a particular embodiment or aspect of the present invention consists of or is essentially derived from such elements, features, etc. For brevity, these embodiments are not, in all cases, specifically described in many words herein. It should also be understood that any embodiment or aspect of the present invention may be expressly excluded from the claims, regardless of whether specific exclusions are enumerated in the specification. Publications, websites, and other reference materials referenced herein to provide background to the present invention and further details relating to its implementation are incorporated herein by reference.

Claims

1. A therapeutic composition comprising recombinant insulin-like growth factor-1 (IGF-1) and recombinant insulin-like growth factor-binding protein-3 (IGFB-3) for treating, including preventing, bronchopulmonary dysplasia (BPD) in premature infants, The IGF-1 and IGFBP-3 are complexed in equimolar amounts before administration, and The composition is administered by continuous intravenous infusion at a dose of 400-500 micrograms / kg / 24 hours from birth to approximately 24-34 weeks postmenstrual age (PMA). Therapeutic composition.

2. The therapeutic composition according to claim 1, wherein the dose is 400 micrograms / kg / 24 hours.

3. The therapeutic composition according to claim 1 or 2, wherein the premature infant is an extremely premature infant.

4. The therapeutic composition according to any one of claims 1 to 3, wherein the premature infant was born at least three months early.

5. A therapeutic composition according to any one of claims 1 to 4, which is administered from birth until approximately 28 to 32 weeks of age.

6. A therapeutic composition according to any one of claims 1 to 5, which is administered from birth until approximately 29 weeks and 6 days of PMA.

7. The therapeutic composition according to any one of claims 1 to 6, wherein the premature infant has a reduced IGF-1 serum level.

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