Methods and compositions for treating chronic lung diseases

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 APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 557,113, filed September 11, 2017, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] background An estimated 4.2 million babies are born in the United States each year, of which approximately 383,000 (about 9%) are born prematurely. Preterm labor and its complications are a major perinatal public health challenge in developed countries today. Infants born prematurely and with low birth weight miss most of the critical period of intrauterine development. These complications account for half of all infant deaths and three-quarters of long-term morbidity. The specialized care and associated high costs required during the neonatal period and throughout the life of survivors place a heavy burden on national finances. Many survivors also experience a reduced quality of life due to physical damage directly resulting from prematurity.

[0003] Normal pregnancy and gestational age is considered 40 weeks (280 days) from the date of conception. Infants born before 37 weeks of gestation are considered premature and may be at risk for complications. Advances in medical technology have made it possible for infants born as early as 23 weeks of gestation (17 weeks premature) to survive. Infants born prematurely are at high risk for death or serious complications due to low birth weight and immature body systems. Low birth weight, defined as a cutoff of 2,500 g, serves as a marker for high-risk newborns. Low birth weight is correlated with prenatal risk factors, intrapartum complications, and neonatal illnesses and accounts for a large proportion of preterm births. Studies of extremely low birth weight have established cutoffs of less than 1,500 g or less than 1,000 g, which identify high-risk infants with a high incidence 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)).

[0004] The lungs, digestive tract, and nervous system (including the brain) are not fully developed in premature infants, making them particularly vulnerable to complications. The most common medical problems faced by premature infants are retinopathy of prematurity, growth retardation, mental retardation, 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 those born extremely preterm, are at high risk for developing chronic lung disease associated with bronchopulmonary dysplasia (BPD) during early manifestation. The long-term trajectory of pulmonary outcomes in infants born extremely prematurely typically begins with prenatal risk factors, develops respiratory distress syndrome (RDS) requiring respiratory support in the hours or days after birth, develops into a diagnosis of BPD in those who survive to term equivalence, and ultimately develops chronic respiratory morbidity (CRM) as they grow into infancy, early childhood, and often school-age or adolescence. CRM frequently results in respiratory readmissions and emergency room visits, requires respiratory medications or home respiratory support, and many suffer from airway hyperresponsiveness, limiting their quality of life. Although the majority of infants with BPD at 36 weeks develop persistent lung disease at a corrected age of 12 to 24 months, some infants develop chronic lung disease later in infancy without being 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) Summary of the Invention

[0007] overview The present invention provides an effective treatment for chronic lung disease (CLD) of premature infants. The invention is based, in part, on the discovery that a combination of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) improves not only short-term outcomes but also long-term conditions related to chronic lung disease, thereby significantly improving the growth and developmental arch of extremely prematurely born infants, which begins shortly after birth when maternal IGF-1 supply is depleted and continues until it is replenished.

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

[0009] In some embodiments, the subject in need of treatment is an infant, hi some embodiments, the subject is a premature infant, wherein the infant is 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, a subject in need of treatment is administered a composition comprising IGF-I or an agonist or analog thereof, wherein the composition is administered subcutaneously, intravenously, intramuscularly, or orally. In some embodiments, the IGF-I or an agonist or analog thereof is administered intravenously. In some embodiments, the IGF-I or an agonist or analog thereof is administered at a dose of about 100 to 500 micrograms / kg / 24 hours. In some embodiments, the IGF-I or an agonist or analog thereof is administered at a dose of 100 micrograms / kg / 24 hours to 450 micrograms / kg / 24 hours. In some embodiments, the IGF-I or an agonist or analog thereof is administered at a dose of 150 micrograms / kg / 24 hours to 400 micrograms / kg / 24 hours. In some embodiments, the IGF-I or an agonist or analog thereof is administered at a dose of 200 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 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 about 250 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered at a dose of about 400 micrograms / kg / 24 hours. In some embodiments, IGF-I or its agonist or analog is administered from birth until about 24 to 34 weeks of postmenstrual age (PMA). PMA is defined as the infant's age at the time of discharge from the hospital, at the time of death, or at the first birthday, whichever comes first. PMA is calculated as the sum of (i) total gestational weeks multiplied by 7, (ii) gestational days, and (iii) hospitalization days after birth. In some embodiments, IGF-I or an agonist or analog thereof is administered from birth to about 28-32 weeks PMA, hi some embodiments, IGF-I or an agonist or analog thereof is administered from birth to about 29 weeks + 6 days PMA.

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

[0012] In some embodiments, IGF-1 is recombinantly produced. In some embodiments, IGFBP-3 is recombinantly produced. In some embodiments, IGF-1 and IGFBP-3 are complexed before administration to a 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 an agonist or analog thereof results in a reduced incidence of chronic respiratory morbidity (CRM) by 12 months of corrected age (CA). An infant's corrected age is the infant's age adjusted based on the expected date of delivery. Taking into account a gestational age of 40 weeks (i.e., the expected date of delivery), a premature infant's corrected age is their actual age minus the amount of time they spent outside the mother's body. In some embodiments, administration of IGF-I or an agonist or analog thereof results in a reduced incidence of bronchopulmonary dysplasia (BPD) by 24 weeks to 12 months of postmenstrual age (PMA). For example, administration of IGF-I or an agonist or analog thereof results in a reduced incidence of BPD by 24 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, or 38 weeks, or by 40 weeks, 45 weeks, 50 weeks, or 52 weeks of PMA. In some other embodiments, administration of IGF-I or an agonist or analog thereof results in a reduced incidence of BPD by 6, 8, 10, or 12 months PMA. In some embodiments, administration of IGF-I or an agonist or analog thereof results in a reduced incidence of severe intraventricular hemorrhage (IVH) grade III or IV by 24, 30, 36, 40, 6, 8, 10, or 12 months PMA. In some embodiments, administration of IGF-I or an agonist or analog thereof results in a reduced incidence of retinopathy of prematurity (ROP) by 24, 30, 36, 40, 6, 8, 10, or 12 months PMA.

[0014] The methods disclosed herein include embodiments in which administration of IGF-I or an agonist or analog thereof results in an increase in functional status as assessed by the Prematurity Infant Index (PREMII) by 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 of postmenstrual age (PMA).

[0015] [The present invention 1001] A method of treating chronic lung disease comprising administering to a subject in need thereof insulin-like growth factor-1 (IGF-1) or an agonist or analog thereof. [The present invention 1002] 1001. The method of claim 1001, wherein said IGF-I or an agonist or analog thereof comprises IGF-1 and an IGF binding protein. [The present invention 1003] 1003. The method of claim 1002, wherein said IGF-I or an agonist or analog thereof comprises IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). [The present invention 1004] Any of the aforementioned methods of the present invention, wherein the subject in need of treatment is an infant. [The present invention 1005] Any of the methods of the present invention, wherein the subject is a premature infant. [The present invention 1006] The method of claim 1005, wherein said infant was born at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, or at least 3 months premature. [The present invention 1007] Any of the aforementioned methods of the present invention, wherein the IGF-I or agonist or analog thereof is administered subcutaneously, intravenously, intramuscularly, or orally. [The present invention 1008] 1007. The method of claim 10, wherein said IGF-I or an agonist or analog thereof is administered intravenously. [The present invention 1009] 1008. The method of claim 10, wherein said IGF-I or an agonist or analog thereof is administered at a dose of about 100 to 500 micrograms / kg / 24 hours. [The present invention 1010] 1008. The method of claim 10, wherein said IGF-I or an agonist or analog thereof is administered at a dose of about 250 micrograms / kg / 24 hours. [The present invention 1011] 1008. The method of claim 10, wherein said IGF-I or an agonist or analog thereof is administered at a dose of about 400 micrograms / kg / 24 hours. [The present invention 1012] Any of the methods of the present invention, wherein the IGF-I or agonist or analog thereof is administered from birth until about 24-34 weeks postmenstrual age (PMA). [The present invention 1013] Any of the methods of the present invention, wherein the IGF-I or agonist or analog thereof is administered from birth until about 28-32 weeks PMA. [The present invention 1014] Any of the aforementioned methods of the present invention, wherein said IGF-I or agonist or analog thereof is administered from birth to a PMA of about 29 weeks + 6 days. [The present invention 1015] Any of the aforementioned methods of the present invention, wherein the subject has reduced IGF-1 serum levels. [The present invention 1016] 1015. The method of claim 10, wherein said reduced IGF-1 serum level is about 30-50 micrograms / L. [The present invention 1017] Any of the aforementioned methods of the present invention, wherein the IGF-1 is recombinantly produced. [The present invention 1018] The method of any one of claims 1003 to 1017, wherein said IGFBP-3 is recombinantly produced. [The present invention 1019] The method of any of claims 1003 to 1018, wherein said IGF-1 and said IGFBP-3 are complexed prior to administration to said subject. [The present invention 1020] 1019. The method of claim 1019, wherein said IGF-1 and IGFBP-3 are complexed in equimolar amounts. [The present invention 1021] Any of the aforementioned methods of the present invention, wherein administration of said IGF-I or an agonist or analog thereof results in a reduced incidence of Chronic Respiratory Morbidity (CRM) by 12 months corrected age (CA). [The present invention 1022] Any of the methods of the present invention, wherein administration of the IGF-I or agonist or analog thereof results in a reduced incidence of bronchopulmonary dysplasia (BPD) by 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months of postmenstrual age (PMA). [The present invention 1023] Any of the methods of the present invention, wherein administration of the IGF-I or agonist or analog thereof results in a reduced incidence of severe intraventricular hemorrhage (IVH) grade III or IV by 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months of postmenstrual age (PMA). [The present invention 1024] Any of the methods of the present invention, wherein administration of the IGF-I or agonist or analog thereof results in a reduced incidence of retinopathy of prematurity (ROP) by 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months of postmenstrual age (PMA). [The present invention 1025] Any of the methods of the present invention, wherein administration of the IGF-I or an agonist or analog thereof results in an increase in functional status as assessed by the Prematurity Infant Index (PREMII) by 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months of postmenstrual age (PMA). While the present invention has been described in connection with certain preferred embodiments, it should be understood that the foregoing and the following examples are illustrative of 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 apparent to those skilled in the art to which the invention pertains. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description 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, particularly extremely preterm infants. In some embodiments, the methods of the present invention comprise administering insulin-like growth factor-1 (IGF-1) or an agonist or analog thereof to a subject in need of treatment (e.g., a premature infant). In some embodiments, the IGF-1 or an agonist or analog thereof 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 sections is not meant to limit the present invention. Each section may be applicable to any aspect of the present invention. In this application, the use of "or" means "and / or" unless stated otherwise.

[0018] definition "Preterm" or "premature" or "premature" or "premature infant" or "premature newborn" or grammatical equivalents refer to a patient being born before 40 weeks of gestation or weighing 10% below average for the patient's gestational age. In some embodiments, a premature infant refers to an infant born at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, or at least 3 months early.

[0019] "IGF-I" refers to insulin-like growth factor I from any species, including bovine, ovine, porcine, equine, and human, preferably human, or, if referring to exogenous administration, to insulin-like growth factor I from any species, whether natural, synthetic, or recombinant, provided that it is bound to an IGF-binding protein at the appropriate site. IGF-I can be produced recombinantly, for example, as described in PCT Publication WO 95 / 04076.

[0020] "IGFBP" or "IGF-binding protein" refers to a protein or polypeptide from the insulin-like growth factor-binding protein family that is normally associated with, binds to, or complexed with IGF-I, whether circulating or not (i.e., in serum or tissues). This binding protein does not include receptors. 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).Other identified IGFBPs are described, for example, in EP 375,438 published June 27, 1990; EP 369,943 published May 23, 1990; WO 89 / 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, e.g., 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 be from any species, including bovine, ovine, porcine, and human, and may be native sequence or a variant form, including but not limited to, a naturally occurring allelic variant. IGFBP-3 may be from any source, whether natural, synthetic, or recombinant, provided that it binds to IGF-I at the appropriate site. IGFBP-3 may be produced recombinantly, as described in PCT Publication WO 95 / 04076.

[0022] As used herein, a "therapeutic composition" is defined as comprising IGF-I, its analogs, or IGF-I in combination with its binding protein, IGFBP-3 (IGF-I / IGFBP-3 complex). Therapeutic compositions may also include other substances, such as water, minerals, carriers, e.g., proteins, and other excipients known to those skilled in the art.

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

[0024] An "agonist" of IGF-I is a compound, including peptides, that is capable of increasing serum and tissue levels of IGF, particularly IGF-I, in mammals, particularly humans. See, e.g., U.S. Patent No. 6,251,865 for a discussion of IGF agonist molecules.

[0025] As used herein, "developmental delay" refers to abnormal neurogenesis that may lead to delayed mental progress in achieving developmental milestones. Developmental delay may, in some cases, be determined by electroencephalogram.

[0026] As used herein, "subject" means any mammal, including a human. In certain embodiments of the invention, the subject is an adult, an adolescent, or a minor. Contemplated by the present invention is the administration of pharmaceutical compositions and / or the performance of treatment methods in utero.

[0027] As used herein, the term "treatment" ("treat" or "treating") refers to any administration of a therapeutic composition (e.g., IGF-1 or an agonist or analog thereof) that partially or completely alleviates, ameliorates, relieves, inhibits, delays the onset of, 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 of subjects who do not exhibit symptoms of the associated disease, disorder, and / or condition and / or who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of subjects who exhibit one or more established signs of the associated disease, disorder, and / or condition.

[0028] As used herein, the terms "improve," "increase," or "reduce," or grammatical equivalents thereof, refer to a value that is compared to a reference measurement, such as, for example, a measurement in the same individual before the initiation of a treatment described herein, or a measurement in a control individual (or control individuals) not receiving a treatment described herein, or a medical history reference or data. A "control individual" is an individual who is approximately the same age as the individual being treated (to ensure that the disease stage in the treated and control individuals is comparable) and who suffers from the same type of chronic lung disease as the individual being treated.

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

[0030] Chronic lung disease in premature infants Very premature babies are at high risk of developing chronic lung disease. Premature babies may need a breathing machine (ventilator) and additional oxygen to breathe. Chronic lung disease occurs when the breathing machine or oxygen injures the premature baby's lungs. Lung injury causes the lining of the newborn's lungs to become inflamed. Tissue is destroyed, and scarring occurs. Scarring can cause breathing difficulties and the newborn may need more oxygen. Lung injury can be caused by: Prematurity: The lungs of premature babies are not fully formed, especially in the alveoli. · Small amounts of surfactant: This is a substance in the lungs that helps keep the tiny alveoli open. · Oxygen use: Too much oxygen can damage cells in the lungs. Mechanical ventilation: Air pressure can damage the lungs. This pressure can come from breathing machines, airway suctioning, and the use of endotracheal (ET) tubes. ET tubes are placed in a newborn's windpipe (trachea) and connected to a breathing machine.

[0031] The long-term trajectory of pulmonary outcomes in infants born extremely prematurely typically begins with prenatal risk factors, develops into respiratory distress syndrome requiring respiratory support in the hours or days after birth, develops into a diagnosis of BPD in those who survive to term, and finally, develops into chronic respiratory morbidity during infancy, early childhood, and often into school-age or adolescence. Chronic respiratory morbidity frequently results in respiratory readmissions and ER visits, requires respiratory medications or home respiratory support, and many suffer from airway hyperresponsiveness, limiting their quality of life.

[0032] IGF-1 or its agonists or analogs The present invention can be practiced using IGF-1 or its agonists or analogs. IGF-I is a known regulator of postnatal growth and metabolism. See Baker J, Liu JP, Robertson EJ, Efstratiadis A. It has a molecular weight of approximately 7.5 kilodaltons (Kd). Most circulating IGFs bind 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 an 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 IGF-I binding proteins such as IGFBP-3 can be purified from natural sources or produced by recombinant means.For example, the purification of IGF-I from human serum is known in the art (Rinderknecht et al. (1976) Proc.Natl.Acad.Sci.USA 73:2365-2369).The production of IGF-I by recombinant methods is shown in EP0128-733 published in December 1984.IGFBP-3 can be purified from natural sources, for example, using the method shown in Baxter et al. (1986, Biochem.Biophys.Res.Comm.139:1256-1261). Alternatively, IGFBP-3 may be recombinantly synthesized as discussed in Sommer et al., pp. 715-728, Modern Concepts Of Insulin-Like Growth Factors (E S Pencer, ed., Elsevier, NY, 1991). Recombinant IGFBP-3 binds to IGF-I at a 1:1 molar ratio.

[0035] Pharmaceutical Compositions and Therapeutic Uses The present invention provides compositions and methods for treating patients suffering from chronic lung disease (CLD), particularly CLD associated with prematurity. For example, the present invention may be used to treat premature infants suffering from CLD or complications associated with CLD. In some embodiments, the present invention may be used to treat infants born at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, or at least 3 months prematurely. In some embodiments, the present invention may be used to treat extremely premature infants.

[0036] In one embodiment of the 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] Compositions containing equimolar amounts of IGF-I and IGF binding protein may be used. In some embodiments, IGF-I and IGF binding protein are complexed prior to administration. The 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 time sufficient to form an equimolar complex. In some embodiments, recombinant human IGF-I and recombinant human IGF binding protein are combined to form the complex during purification, as described in International Patent Application No. WO 96 / 40736.

[0038] For therapeutic use, IGF-I or an analog thereof may be suitably administered to a patient alone or as part of a pharmaceutical composition comprising IGF-I or an analog thereof together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0039] The pharmaceutical compositions of the present invention include those suitable for oral administration, nasal administration, topical administration (including buccal administration and sublingual administration), or parenteral administration (including subcutaneous administration, intramuscular administration, intravenous administration, and intradermal administration).The formulations may be 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 preparative methods include the step of bringing into association the molecule to be administered with the carrier(s), which constitute one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or all of these, and then, if necessary, shaping the product.

[0041] Compositions of the present invention suitable for oral administration may be presented as discrete units such as, for example, 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, or as an oil-in-water or water-in-oil liquid emulsion, or encapsulated in liposomes, and as a bolus.

[0042] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing the active ingredient in a free-flowing form, such as powder or granules, with optional binders, lubricants, inert diluents, preservatives, surfactants, or dispersants, and compressing them in a suitable machine. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or marked, and may be formulated to provide slow or controlled release of the active ingredient contained therein.

[0043] Compositions suitable for parenteral administration include aqueous or nonaqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient. Also included are aqueous or nonaqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored under freeze-dried / lyophilized conditions requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions 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 analogs or agonists, or IGF-I or analogs in combination with IGF-binding protein complexes to infants in need of 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 agonists, or analogs are preferably administered orally. IV, IM, SC, and IP administration may be by bolus or infusion, or by sustained-release implantable devices, including, but not limited to, pumps, sustained-release formulations, and mechanical devices. The formulation, route and method of administration, and dosage depend on the disorder being treated and the patient's medical history. In some embodiments, IGF-I or its agonists or analogs are administered intravenously.

[0045] Pharmaceutical compositions according to the present invention can be administered at various dosages. For example, a suitable dose may range from about 100 to 500 micrograms / kg / 24 hours. In some embodiments, a suitable dose may be about or greater than 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. In some embodiments, pharmaceutical compositions according to the present invention are administered from birth until about 24 to 34 weeks of postmenstrual age (PMA), until about 28 to 32 weeks of PMA, or until about 29 weeks + 6 days of PMA.

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

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

[0048] For parenteral or oral administration, the conjugate composition may be in a semi-solid or liquid form, e.g., a liquid, suspension, or the like. Physiologically compatible carriers are those that are non-toxic to recipients at the dosages and concentrations employed and are 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. Physiologically compatible carriers therefore include, but are not limited to, saline, serum albumin, 5% dextrose, plasma preparations, and other protein-containing solutions. Optionally, the carrier may also include a detergent or surfactant.

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

[0050] Finally, an article of manufacture is provided that includes packaging material and a pharmaceutical agent contained within the packaging material. The packaging material includes a label indicating that the pharmaceutical agent can be administered in an effective amount and for a sufficient period of time to treat and / or prevent complications associated with preterm birth. The pharmaceutical agent includes IGF-I, an agonist, or an analog thereof, along with a pharmaceutically acceptable carrier.

[0051] The present invention is further illustrated by the following examples, which are intended to be exemplary of the invention. [Example]

[0052] Example 1. Treatment of CLD in extremely preterm infants This investigational agent, containing an insulin-like growth factor-1 / insulin-like growth factor binding protein-3 (rhIGF-1 / rhIGFBP-3) complex, was tested for its therapeutic efficacy in treating chronic lung disease (CLD). This study was a multicenter, randomized, open-label, controlled, three-arm study designed to evaluate the clinical efficacy and safety of a therapeutic composition in preventing chronic lung disease in humans. The study was conducted in subjects up to 12 months corrected age (CA) and compared with standard neonatal care for extremely preterm infants. The study was reviewed and approved by the responsible institution's Institutional Review Board (IRB) / Internal Review Board (IEC).

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

[0054] Subjects Subjects will have a gestational age (GA) of 23 weeks + 0 days to 27 weeks + 6 days. Subjects will include both males and females. At least 50 subjects will be included in the study.

[0055] Exclusion criteriaExclusion criteria include detectable gross congenital anomalies, known or suspected chromosomal abnormalities, genetic disorders, or genetic syndromes, in the opinion of the investigator. Exclusion criteria also include a persistent blood glucose level of less than 2.5 millimoles per liter (mmol / L) at the baseline visit to exclude severe congenital abnormalities of glucose metabolism; clinically significant neurological disease, in the opinion of the investigator; monozygotic multiples; and any other condition that may pose a risk to the subject or interfere with the subject's ability to comply with the protocol or interpret the results. Subjects will be excluded if they are participating or planning to participate in a clinical trial of another investigational drug, device, or method (participation in observational studies will be permitted on a case-by-case basis). Subjects will also be excluded if they or their parents or legally authorized representatives are unable to comply with the protocol or are not likely to be available for the long-term follow-up period determined by the investigator.

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

[0057] One group of subjects (Group A) will receive 250 micrograms / kg / 24 hour therapeutic composition intravenously (IV) from birth until 29 weeks + 6 days of postmenstrual age (PMA). Another group of subjects (Group B) will receive 400 micrograms / kg / 24 hour therapeutic composition intravenously (IV) from birth until 29 weeks + 6 days of postmenstrual age (PMA). A third group (Group C or control group) will receive standard neonatal treatment only.

[0058] The primary outcome measured is the incidence of chronic respiratory morbidity (CRM) by 12 months corrected age (CA) [time frame: baseline to 12 months corrected age (CA)]. CRM is a common adverse outcome in premature infants, resulting in recurrent respiratory symptoms requiring treatment with pulmonary medications, e.g., bronchodilators, and requiring home oxygen supplementation, frequent emergency room visits, or hospital readmissions, particularly during the first year of life. CRM is measured by respiratory care utilization and respiratory symptoms.

[0059] Secondary outcomes included the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA) [time frame: 36 weeks PMA]. BPD is a chronic lung disorder characterized by pulmonary immaturity, undifferentiated alveoli with the presence of hyaline membranes and pulmonary diastole, dilated capillaries bathed in mesenchyme, and distorted deposition of extracellular matrix. BPD has a residual impact on lung function and has been associated with neurodevelopmental problems later in childhood.

[0060] Secondary outcomes also include: Incidence of severe intraventricular hemorrhage (IVH) grade III or IV up to 40 weeks postmenstrual age (PMA) [time frame: 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 morbidity (CRM) or death by 6 months corrected age (CA) [Time frame: 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, e.g., bronchodilators, and requiring home oxygen supplementation, frequent emergency room visits, or hospital readmissions, particularly during the first year of life. CRM is measured by utilization of respiratory care and respiratory symptoms. Functional status as assessed by the Prematurity Index (PREMII) at 40 weeks' postmenstrual age (PMA) [Timeframe: 36 weeks' PMA]. PREMII is a Clinician-Reported Outcome (ClinRO) assessment used to capture the overall functional maturation of extremely preterm infants. Functional status is defined as what the infant is able to do in eight key areas of function (feeding, weight gain, temperature regulation, respiratory support, apnea, bradycardia, desaturation events, and oxygen administration) as a reflection of the infant's overall health and development.

[0061] Example 2. Prevention of BPD in extremely preterm infants A randomized, parallel-group, controlled trial of the efficacy of IGF-1 / IGFBP3 in preventing BPD was conducted between June 18, 2010, and March 30, 2016, at multiple sites in Italy, the Netherlands, Poland, Sweden, the United Kingdom, and the United States.

[0062] The IGF-1 / IGFBP-3 drug mecasermin rinfabate was administered as a continuous intravenous infusion to subjects from study day 0 (birthday) until 29 weeks + 6 days postmenstrual age (PMA), when the subject's endogenous IGF-1 production was deemed sufficient to maintain physiological serum IGF-1 levels. After the infusion of the study drug was stopped, each subject was followed until 40 weeks ± 4 days postmenstrual age (PMA). This study aimed to determine the dose of rhIGF-1 / rhIGFBP-3 administered as a continuous infusion (CI) required to establish and maintain long-term serum IGF-1 levels within the physiological range in premature infants to prevent retinopathy of prematurity. This was a phase II, randomized, controlled, assessor-blinded, dose-confirmation, pharmacokinetic, safety, and efficacy study of rhIGF-1 / rhIGFBP-3. Sixty-one subjects received 250 micrograms per kilogram (mcg / kg) of insulin-like growth factor I (rhIGF-I) / insulin-like growth factor binding protein-3 (rhIGFBP-3) over 24 hours by continuous intravenous (IV) infusion from day 0 to postmenstrual age (PMA) 29 weeks 6 days. As a control group, 60 subjects received standard care alone. Table 1 shows the overall study flow of subjects.

[0063] (Table 1) Subject flow: Overall study TIFF2025114869000001.tif67160

[0064] Table 2 shows the study population.

[0065] (Table 2) TIFF2025114869000002.tif79170

[0066] Ongoing secondary outcomes of this study specifically included the following parameters: · Time to discharge from neonatal intensive care (TDNIC) [time frame: day 0 to 40 weeks postmenstrual age (EOS)]. Number of subjects with bronchopulmonary dysplasia (BPD) [time frame: at 36 weeks postmenstrual age]. · The severity of BPD as mild, moderate, and severe was based on the National Institute of Child Health and Human Development (NICHD) guidelines for premature infants born at less than 32 weeks gestational age (GA). Mild: Requires oxygen for the first 28 days, but is placed on room air at 36 weeks PMA or discharged home, whichever comes first. Moderate BPD: Requires oxygen for the first 28 days, but requires less than 30 percent (%) oxygen at 36 weeks PMA or discharged home, whichever comes first. Severe BPD: Requires oxygen for the first 28 days and (≥) 30% oxygen via head hood or nasal cannula, or continuous positive airway pressure, or mechanical ventilation, or high-flow nasal cannula at ≥ 2 L / min at 36 weeks PMA or discharge home, whichever occurs first. Percent weight change [Time frame: Day 0 - 40 weeks postmenstrual age (EOS)]. Percent change is the specific weight change in kilograms (kg) per day. · Percent change in height [time frame: day 0 to 40 weeks postmenstrual age (EOS)]. Rate of change is height change in centimeters (cm) per day. Number of subjects with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) [time frame: Day 0 to 40 weeks postmenstrual age (EOS)]. An adverse event (AE) was any untoward medical occurrence in a subject receiving a study drug, regardless of possible causality. A serious adverse event (SAE) was an AE that led to any of the following outcomes or was considered serious for any other reason: death; initial hospitalization or prolonged length of hospital stay in an inpatient; life-threatening event (imminent risk of death); persistent or significant disability / incapacity; or congenital abnormality. A treatment-emergent adverse event was defined as the occurrence of an AE, or a worsening of the severity of a pre-existing AE, either on the day of the first dose of study product or later. Percentage of serum IGF-1 concentrations within the target range after rhIGF-1 / rhIGFBP-3 infusion [time frame: day 0 to 40 weeks postmenstrual age (EOS)]. Serum samples were collected from treated and control subjects and IGF-1 quantification was performed using a validated immunoassay method. The target range for serum IGF-1 was 28-109 mcg / L. The percentage of serum IGF-1 levels across treated subjects falling within the range was reported. Serum concentrations of IGFBP-3 after intravenous (IV) infusion of rhIGF-1 / rhIGFBP-3 [time frame: day 0 to 40 weeks postmenstrual age]. Serum concentrations of acid-labile subunit (ALS) following intravenous (IV) infusion of rhIGF-1 / rhIGFBP-3 [time frame: day 7 to 40 weeks postmenstrual age].

[0067] Table 3 shows the BPD values measured as secondary outcomes.

[0068] (Table 3) TIFF2025114869000003.tif84160

[0069] No statistical analysis was presented regarding the number of subjects with bronchopulmonary dysplasia (BPD).

[0070] While the particular compounds, compositions and methods described herein are described with specificity according to particular embodiments, the following examples are intended to illustrate, but not limit, the compounds of the invention.

[0071] As used in this specification and claims, the articles "a" and "an" should be understood to include plural referents unless clearly indicated to the contrary. A claim or description including "or" between one or more members of a group is deemed satisfied when one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless the context indicates otherwise. The invention includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which two or more, or all, of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the invention should be understood to encompass all variations, combinations, and permutations of one or more limitations, elements, phrases, descriptive terms, etc. from one or more of the enumerated claims introduced into other claims dependent on the same base claim (or any other related claim) unless otherwise indicated or unless a contradiction or inconsistency would arise to one of ordinary skill in the art. Where elements are presented as a list (e.g., a Markush group or similar format), it should be understood that each subgroup of elements is also disclosed, and that any element may be removed from the group. Generally, the invention or aspects of the invention are referred to as including certain elements, features, etc., and it should be understood that certain embodiments of the invention or aspects of the invention consist of, or consist essentially of, such elements, features, etc. For the sake of brevity, these embodiments have not in all instances been specifically described in so many words herein. It should also be understood that any embodiment or aspect of the invention can be expressly excluded from the claims, regardless of whether a specific exclusion is recited in the specification. Publications, websites, and other reference materials referenced herein to describe the background of the invention and to provide further details regarding its practice are incorporated herein by reference.

Claims

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

2. The therapeutic composition described in 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 of any one of claims 1 to 3, wherein the premature infant is born at least three months prematurely.

5. The therapeutic composition of any one of claims 1 to 4, administered from birth until about 28-32 weeks PMA.

6. 6. The therapeutic composition of any one of claims 1 to 5, administered from birth to about 29 weeks PMA+6 days.

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