EA044079B1 - METHODS AND COMPOSITIONS INTENDED FOR TREATMENT OF CHRONIC LUNG DISEASES - Google Patents

Description

Cross reference to related applications

This application claims benefit from U.S. Provisional Patent Application No. 62/557113, filed September 11, 2017, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Of the approximately 4.2 million live births in the United States each year, approximately 383,000 (approximately 9%) are born prematurely. Currently, preterm birth and its complications are the main problems of the perinatal public health system in developed societies. Low birth weight babies or babies born prematurely miss most of the critical period of intrauterine growth. They account for half of all infant deaths and three quarters of long-term deaths. They place a heavy burden on the national economy due to the high cost of specialized care both in the neonatal period and throughout the life of the survivors. Many survivors also have a reduced quality of life due to the physical damage caused directly by prematurity.

The duration of physiological pregnancy or gestation is considered to be 40 weeks (280 days) from the date of conception. Babies born before 37 weeks' gestation are considered premature and may be at risk for complications. Advances in medical technology make it possible for infants born at 23 weeks gestational age (17 weeks preterm) to survive. Infants born prematurely are at high risk of death or severe complications due to their low birth weight and the immaturity of their body systems. Low birth weight, defined as a cutoff of 2500 g, serves as a marker of high risk for newborns, as it is correlated with prenatal risk factors, intrauterine complications and neonatal diseases, and is significantly associated with preterm birth. Studies of very low birth weight infants, defined as a cutoff of less than 1500 g or less than 1000 g, have identified the highest-risk infants as those with a high incidence of severe respiratory and neurological complications associated with extreme prematurity. (See, Hack, M., Klein, N.K., & Taylor, H.G., Longterm developmental outcomes of low birth weight infants. The Future of Children, 5,176-196 (1995)).

The lungs, digestive system, and nervous system (including the brain) are not fully developed in premature babies and are especially vulnerable to complications. The most common medical problems encountered in premature infants are retinopathy of prematurity, failure to thrive, mental retardation, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, and ventricular hemorrhage.

Chronic lung disease (CLD) is a particularly severe and life-threatening condition in premature infants. Premature infants, particularly those with extreme prematurity, are at very high risk of developing chronic lung disease with early onset bronchopulmonary dysplasia (BPD). Long-term pulmonary sequelae in infants born with extreme prematurity typically begin with antenatal risk factors followed by respiratory distress syndrome (RDS) in the first hours or days of life requiring ventilatory support, leading to a diagnosis of BPD in those infants who survive for an equivalent period of time, and eventually to chronic respiratory diseases as they progress through infancy, early childhood, and often even into school age or puberty, leading to more frequent readmissions and ER visits due to respiratory problems tract, the need for respiratory medications or home ventilatory support, with many suffering from a form of reactive airway disease that continues to limit their quality of life. A significant proportion of infants with BPD at 36 weeks develop persistent lung disease at corrected ages of 12–24 months, but there are also infants without a diagnosis of BPD who develop chronic lung disease later in infancy.

Short description

The present invention provides an effective treatment for chronic lung disease (CLD) in premature infants. The present invention is based in part on the understanding that the combination of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) can improve not only short-term outcomes, but also long-term conditions associated with chronic lung disease, resulting in to significantly improved growth and development of infants born with extreme prematurity, starting immediately after birth when they are deprived of the maternal source of IGF-1, through its replacement.

In one aspect of the present invention there is provided a method of treating chronic lung disease (CLD) comprising administering to a subject in need of treatment a composition comprising insulin-like growth factor-1 (IGF-1) or an agonist or analog thereof. In some embodiments, a method of treating CLD is provided, comprising administering to a person in need of treatment

- 1 044079 to the subject of a composition containing IGF-I or an agonist or analogue thereof, containing IGF-1 and an IGF-binding protein. In some embodiments, the composition contains IGF-I or an agonist or analog thereof, and also contains IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3).

In some embodiments, the subject in need of treatment is an infant. In some embodiments, the subject is a premature infant, where the infant is born at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 10 weeks, or 3 months premature.

In some embodiments, a composition comprising an IGF-I, or agonist, or analogue is administered to a subject in need of treatment, wherein the composition is administered subcutaneously, intravenously, intramuscularly, or orally. In some embodiments, IGF-I or an agonist or analogue thereof is administered intravenously. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose of from about 100 to 500 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose ranging from 100 micrograms/kg/24 hours to 450 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose ranging from 150 micrograms/kg/24 hours to 400 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose ranging from 200 micrograms/kg/24 hours to 400 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose ranging from 250 micrograms/kg/24 hours to 400 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose of approximately 250 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered at a dose of approximately 400 micrograms/kg/24 hours. In some embodiments, IGF-I or an agonist or analogue thereof is administered from birth to postconceptional age (PCA) of approximately 24-34 weeks. PMA is defined as the infant's age in weeks when he or she is discharged from the hospital, or the age at death, or the first birthday, whichever occurs first. It is calculated as the sum of (i) all weeks of gestation multiplied by seven, (ii) the number of days of gestation, and (iii) days of hospital stay after birth. In some embodiments, IGF-I or an agonist or analogue thereof is administered from birth to PMA of about 28 to 32 weeks. In some embodiments, IGF-I or an agonist or analogue thereof is administered from birth to PMA of approximately 29 weeks plus 6 days.

In some embodiments of the present invention, the subject has reduced serum IGF-1 levels. In some embodiments, the reduced serum IGF-1 levels are below 60 micrograms/L. In some embodiments, the reduced serum IGF-1 levels are below 50 micrograms/L. In some embodiments, the reduced serum IGF-1 levels are below 40 micrograms/L. In some embodiments, the reduced serum IGF-1 levels are from about 30 to 50 micrograms/L.

In some embodiments, IGF-1 is produced recombinantly. In some embodiments, IGFBP-3 is produced recombinantly. 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.

The method presented herein provides embodiments wherein administration of IGF-I or an agonist or analogue results in a reduction in the incidence of chronic respiratory complication (CRM) up to 12 months corrected age (CA). Infant age at gestational age is the adjusted age of the infant based on his or her date of birth. If we assume that the gestation period should be 40 weeks (i.e., the expected date of birth), then the age of a prematurely born baby, taking into account the period of intrauterine development, is calculated by subtracting from its real age the excess time that it spent outside the mother's body. In some embodiments, administration of IGF-I or an agonist or analog results in a reduction in the incidence of bronchopulmonary dysplasia (BPD) to a postconceptional age (PCA) of 24 weeks to 12 months. For example, administration of IGF-I or an agonist or analogue results in a reduction in the incidence of BPD 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 an agonist or analog results in a reduction in the incidence of BPD to a PMA of 6 months, 8 months, 10 months, or 12 months. In some embodiments, administration of IGF-I or an agonist or analogue thereof results in a reduction in the incidence of grade III or IV severe ventricular hemorrhage (IVH) up to postconceptional age (PCA) of 24 weeks, 30 weeks, 36 weeks, 40 weeks, 6 months, 8 months, 10 months or 12 months. In some embodiments, administration of IGF-I or an agonist or analog thereof results in a reduction in the incidence of retinopathy of prematurity (ROP) until postconceptional age (PCA) of 24 weeks, 30

- 2 044079 weeks, 36 weeks, 40 weeks, 6 months, 8 months, 10 months or 12 months.

The method disclosed herein provides embodiments wherein administration of IGF-I or an agonist or analogue results in an increase in performance status, as assessed by the Prematurity Infant Index (PREMII), to a postconceptional age (PCA) 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.

It should be understood that although the present invention has been described in connection with its preferred specific embodiments, the foregoing description, as well as the following examples, are intended to illustrate and not to limit the scope of the present invention. Other aspects, advantages and modifications within the scope of the present invention will be apparent to those skilled in the art to which the present invention relates.

Detailed description

The present invention provides methods and compositions for the treatment of chronic lung disease. The compositions and methods presented herein are particularly effective for the treatment of chronic lung disease in premature infants, especially in infants with extreme prematurity. In some embodiments, the method of the present invention comprises administering insulin-like growth factor-1 (IGF-1) or an agonist or analog thereof to a subject in need of treatment (eg, a premature infant). In some embodiments, IGF-I or an agonist or analog thereof comprises IGF-1 and an IGF-binding protein (eg, insulin-like growth factor binding protein-3 (IGFBP-3)).

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

Definitions.

Premature, or premature birth, or prematurity, or premature infant, or preterm child, or grammatical equivalents refer to the birth of a patient before 40 weeks of gestation or a patient whose body weight is 10% less than the average body weight for the patient's gestational age. In some embodiments, a preterm infant means an infant who was born at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, or 3 months premature.

IGF-I means insulin-like growth factor I of any kind, including bovine, ovine, porcine, equine and human, but preferably human, and, if the term refers to exogenous administration, then from any source, whether natural, synthetic or recombinant, provided that it binds to the IGF-binding protein at the appropriate site. IGF-I can be produced recombinantly, for example as described in PCT publication WO 95/04076.

IGFBP or IGF-binding protein means a protein or polypeptide from the family of insulin-like growth factor binding proteins typically associated with, bound to, or complexed with IGF-I, whether circulating or not (i.e., in blood serum or tissue). Such binding proteins do not include receptors. This definition includes IGFBP-1, IGFBP2, 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 IGFBP. Mac 25 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 375438, published June 27, 1990; EP 369943, published May 23, 1990; WO 89/09268, published October 5, 1989; Wood et al., Molecular Endocrinology, 2: 1176-1185 (1988); Brinkman et al., EMBO J., 7: 2417-2423 (1988); Lee et al., Mol. Endocrinol., 2: 404-411 (1988); Brewer et al., BBRC, 152: 1289-1297 (1988); EP 294021, published December 7, 1988; Baxter et 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., al. 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).

IGFBP-3 stands for insulin-like growth factor binding protein 3. IGFBP-3 is a member of the insulin-like growth factor binding protein family. IGFBP-3 can be of any species, including bovine, ovine, porcine and human, as a native sequence or variant, including without limitation allelic variants found in nature. IGFBP-3 can be from any source, be it natural, synthetic or recombinant, as long as it binds IGF-I at the appropriate sites. IGFBP-3 can be produced recombinantly as described in PCT publication WO 95/04076.

As used herein, the term therapeutic composition is defined as a composition containing IGF-I, an analogue thereof, or IGF-I in combination with its binding protein IGFBP-3 (IGF-I7IGFBP-3 complex). The therapeutic composition may also contain other substances such as water, minerals, carriers such as proteins, and other excipients known to one skilled in the art.

IGF-I analogues are compounds that exhibit the same therapeutic effect as IGF-I in humans or animals. They may be naturally occurring IGF-I analogs (eg, truncated IGF-I) or any of the known synthetic IGF-I analogs. See, for example, US Pat. No. 5,473,054 for IGF-I analog compounds.

IGF-I agonists are compounds, including peptides, that are capable of increasing serum and tissue levels of IGF, in particular IGF-I, in mammals and, in particular, in humans. See, for example, US Pat. No. 6,251,865 for IGF agonist molecules.

As used herein, the term developmental delay will refer to pathological neurogenesis that has the potential to cause mental retardation in achieving developmental milestones. In some cases, developmental delay can be determined using an electroencephalogram.

As used herein, the term subject means any mammal, including humans. In certain embodiments of the present invention, the subject is an adult, adolescent, or infant. The present invention also provides for the administration of pharmaceutical compositions and/or methods of treatment in utero.

As used herein, the term treatment (also treat or treat) means any administration of a therapeutic composition (eg, IGF-1 or an agonist or analogue thereof) that partially or completely mitigates, improves, attenuates, suppresses, delays the onset of, prevents, reduces severity and/or reduces the frequency of occurrence of one or more symptoms or signs of a particular disease, disorder and/or condition (eg, chronic lung disease). Such treatment may be administered to a subject who is not showing signs of the corresponding disease, disorder and/or condition, and/or to a subject who is showing only early signs of the disease, disorder and/or condition. Alternatively or additionally, such treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.

As used herein, the expressions improve, increase, or decrease, or its grammatical equivalents, indicate values that are compared with values obtained from a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in control individual (or multiple control individuals) in the absence of treatment described herein or historical background or data. A control individual is an individual affected by the same form of chronic lung disease as the treated individual, who is approximately the same age as the treated individual (which ensures that the disease stages of the treated individual and the control individual(s) are comparable) ).

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 in infants, particularly preterm or extreme prematurity infants. CLD includes a spectrum of diseases and disorders including, but not limited to, COPD (emphysema and chronic bronchitis), asthma, cystic fibrosis, restrictive lung disease, and chronic infections.

Chronic lung disease in premature infants.

Infants with extreme prematurity have a very high risk of developing chronic lung disease. Premature babies may need a breathing machine (ventilator) and extra oxygen to breathe. Chronic lung disease occurs when the breathing apparatus or oxygen damages the lungs of a premature baby. When the lungs are damaged, the tissues inside the baby's lungs become inflamed. The tissue may break down, resulting in scarring. The scarring may make it difficult to breathe and the baby may need more oxygen. Lung damage can be caused by the following:

Prematurity: A premature baby's lungs are not fully formed. This primarily applies to the alveolar sacs.

Low amounts of surfactant: This is a substance in the lungs that helps keep the small alveolar sacs open.

Oxygen use: High amounts of oxygen can damage lung cells.

Breathing apparatus (ventilator): Atmospheric pressure can damage the lungs. This pressure can be generated by breathing machines, airway suction, and the use of an endotracheal (ET) tube. An ET tube is a tube placed in your child's airway (trachea) and connected to a breathing machine.

Long-term pulmonary sequelae in infants born with extreme prematurity typically begin with antenatal risk factors followed by respiratory distress syndrome (RDS) in the first hours or days of life requiring ventilatory support, leading to a diagnosis of BPD in the infant. those infants who survive for an equivalent period, and eventually to chronic respiratory disease as they grow into infancy, early childhood, and often even into school age or puberty, leading to more frequent readmissions and ER visits from -respiratory problems, the need for respiratory medications or home ventilator support, with many suffering from a form of reactive airway disease that continues to limit their quality of life.

IGF-1 or its agonist or analogue.

IGF-1 or an agonist or analogue thereof can be used to practice the present invention. IGF-I is a well-known regulator of postnatal growth and metabolism. See, Baker J., Liu J.P., Robertson E.J., Efstratiadis A. It has a molecular weight of approximately 7.5 kilodaltons (kDa). Most circulating IGF is bound to IGF binding protein and, in particular, to IGFBP-3. IGF-I levels can be measured in serum to diagnose growth-related conditions.

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

IGF-I and IGF-I binding proteins, such as IGFBP-3, can be isolated from natural sources or produced using recombinant methods. For example, the isolation of IGF-I from human serum is well 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 EP 0128-733, published in December 1984. IGFBP-3 can be isolated from natural sources using a method such as that described in Baxter et al. (1986, Biochem. Biophys. Res. Comm. 139:12561261). Alternatively, IGFBP-3 can be synthesized recombinantly, as discussed in Sommer et al., pp. 715-728, Modern Concepts Of Insulin-Like Growth Factors (E. M. Spencer, ed., Elsevier, N.Y., 1991). Recombinant IGFBP-3 binds IGF-I in a 1:1 molar ratio.

Pharmaceutical composition and use in therapy.

The present invention provides compositions and methods for treating a patient suffering from chronic lung disease (CLD), in particular CLD associated with prematurity. For example, the present invention can be used to treat a premature infant suffering from CLD or a complication associated with CLD. In some embodiments, the present invention can be used to treat an infant who was born at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, or 3 months premature. In some embodiments, the present invention can be used to treat an infant with extreme prematurity.

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

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. The complex can be formed by mixing approximately equimolar amounts of IGF-I and IGF-binding protein dissolved in physiologically compatible vehicles such as physiological 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 a complex during purification, as described in International Patent Application No. WO 96/40736.

For therapeutic applications, IGF-I or an analogue thereof can be conveniently administered to a patient, alone or as part of a pharmaceutical composition containing IGF-I or an analogue thereof, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be acceptable in terms of its compatibility with the other ingredients of the formulation and not cause harm to the recipient.

The pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, nasal, topical (including buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. For convenience, the formulations may be presented in single dosage dosage form, such as sustained release tablets and capsules, as well as liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing the molecule to be administered into contact with ingredients such as a carrier that includes one or more accessory ingredients. Typically, compositions are prepared by uniformly and directly bringing the active ingredients into contact with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

The compositions of the present invention suitable for oral administration may be presented in the form of individual units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packaged in liposomes, or in the form of a bolus, etc.

A tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable apparatus the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be prepared by molding in a suitable apparatus a mixture of a powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and formulated to provide a slow or controlled release of the active ingredient contained therein.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents and solutions that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in single-dose or multiple-dose containers, such as sealed ampoules and sealed vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, directly before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

The claimed methods disclosed herein provide parenteral and oral administration of IGF-I, an analogue or agonist thereof, or IGF-I or an analogue in combination with a complex of IGF-binding proteins 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 method of the present invention, IGF-I, its agonist or analogue is preferably administered orally. IV, IM, SC, and IP routes of administration may be by bolus or infusion, and may also be administered by an implantable sustained release device, including, but not limited to, pumps, sustained release formulations, and mechanical devices. The composition, route and route of administration, and dosage will depend on the disorder being treated and the patient's medical history. In some embodiments, IGF-I or an agonist or analogue thereof is administered intravenously.

The pharmaceutical composition in accordance with the present invention can be administered in different doses. For example, a suitable dosage may range from about 100 to 500 micrograms/kg/24 hours. In some embodiments, a suitable dosage may be at or greater than 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. In some embodiments, the pharmaceutical composition of the present invention is administered from birth to postconceptional age (PCA) of approximately 24 to 34 weeks, to PCA of approximately 28 to 32 weeks, to PCA of approximately 29 weeks plus 6 days. .

The method presented herein provides embodiments wherein administration of IGF-I or an agonist or analogue results in a reduction in the incidence of chronic respiratory complication (CRM) up to 12 months corrected age (CA). In some embodiments, administration of IGF-I or an agonist or analogue results in a reduction in the incidence of bronchopulmonary dysplasia (BPD) to a postconception age (PCA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months. or 12 months. In some embodiments, administration of IGF-I or an agonist or analog thereof results in a reduction in the incidence of grade III or IV severe ventricular hemorrhage (IVH) up to postconceptional age (PCA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months or 12 months. In some embodiments, administration of IGF-I or an agonist or analog thereof results in a reduction in the incidence of retinopathy of prematurity (ROP) to a postconceptional age (POA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months .

The method disclosed herein provides embodiments wherein administration of IGF-I or an agonist or analogue results in an increase in performance status, as assessed by the Prematurity Infant Index (PREMII), to a postconceptional age (PCA) of 36 weeks. , 40 weeks, 6 months, 8 months, 10 months or 12 months.

For parenteral or oral administration, complex compositions may be semi-solid or liquid preparations such as liquids, suspensions, etc. Physiologically compatible carriers are carriers that are non-toxic to recipients at doses and concentrations used and compatible with the other ingredients of the formulation . For example, the composition preferably does not contain oxidizing agents and other compounds that are known to be destructive to polypeptides. Therefore, physiologically compatible vehicles include, but are not limited to, physiological saline, serum albumin, 5% dextrose, blood plasma preparations, and other protein-containing solutions. Optionally, the carrier may also contain detergents or surfactants.

In yet another aspect, the present invention provides the use of IGF-I, an agonist or analog thereof in the manufacture of a therapeutic composition for treating a complication associated with preterm birth.

Finally, also presented is an article containing packaging material and a pharmaceutical agent in the packaging material. The packaging material contains a label that indicates that the pharmaceutical agent can be administered for an appropriate period at an effective dose for the purpose of treating and/or preventing complications associated with premature birth. The pharmaceutical agent contains IGF-I, its agonist or analogue together with a pharmaceutically acceptable carrier.

The present invention will be further characterized by the following examples, which are intended to illustrate the present invention.

Examples

Example 1: Treatment of CLD in infants with extreme prematurity.

The therapeutic effect in CLD of a clinically tested drug containing the insulin-like growth factor-1/insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) complex was investigated. This study was designed as a multicenter, randomized, open-label, controlled trial with 3 patient groups designed to evaluate the clinical efficacy and safety of the therapeutic composition in preventing the occurrence of chronic lung disease in humans. This study was conducted in subjects up to 12 months of corrected age (CA), comparing with intensive care for neonates with extreme prematurity. This study was reviewed and approved by the implementing agency's institutional review board (IRB)/independent ethics committee (IEC).

Objective: The purpose of this study was to determine whether a clinically tested drug containing rhIGF-1/rhIGFBP-3 (therapeutic composition) was able to reduce respiratory complications in children with extreme prematurity at 12 months of corrected age (CA) compared with extreme prematurity infants receiving only standard neonatal intensive care.

Study Subjects: Subjects had a gestational age (GA) of 23 weeks+0 days and 27 weeks+6 days. Subjects of both sexes were included. At least fifty subjects were included in the study.

Exclusion Criteria: Exclusion criteria included a detectable severe malformation, known or suspected chromosomal abnormality, genetic disorder or syndrome as determined by expert opinion. Exclusion criteria also included persistent blood glucose levels below (<) 2.5 millimoles per liter (mmol/L) at the baseline visit to exclude severe inborn errors of glucose metabolism; clinically manifested neurological disease in accordance with expert opinion; monozygotic twins; 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 interfere with the interpretation of the results. If the subject is participating or is scheduled to participate in a clinical trial of another clinically tested drug, device, or other procedure (participation in observational studies is permitted on a case-by-case basis), then the subject is excluded. If the subject, or parent of the subject,

- 7 044079 or legal representative(s) are unable to comply with the protocol or are likely to be unavailable for long-term follow-up as determined by the investigator, the subject is also excluded.

Detailed description of the clinical trial design: The primary objective of the trial is the prevention of bronchopulmonary dysplasia and chronic lung disease. This study is open-label, with an experimental group being studied in parallel. The controlled conditions will be BPD and CLD.

The therapeutic composition at a dose of 250 micrograms/kg/24 hours was administered to participants in one group (Group A) by intravenous (IV) administration from birth to postconceptional age (PCA) 29 weeks + 6 days. Participants in the other group (Group B) were administered the therapeutic composition at a dose of 400 micrograms/kg/24 hours by intravenous (IV) administration from birth to postconceptional age (PCA) 29 weeks + 6 days. The third group (Group C or control group) of infants received only standard neonatal intensive care.

The primary outcome measure measured was the incidence of chronic respiratory complication (CRM) to 12 months corrected age (CA) [specified time interval: from baseline to 12 months corrected age (CA)]. CRM is a common adverse complication arising from preterm birth, resulting in symptoms of recurrent respiratory disease that require the use of respiratory medications such as bronchodilators, the need for supplemental oxygen at home, frequent visits to the intensive care unit, or readmission to hospital, especially in the first year of life. CRM is measured by the use of medical resources to maintain the respiratory tract and by respiratory symptoms.

Additional efficacy criteria include the incidence of bronchopulmonary dysplasia (BPD) at postconceptional age (PCA) 36 weeks [target time interval: 36 weeks PCA]. BPD is a chronic lung disorder characterized by pulmonary immaturity, undifferentiated alveoli with the presence of hyaline membrane and atelectasis, dilated capillaries embedded in mesenchyme, and distorted deposition of extracellular matrix proteins. BPD results in residual effects on lung function and is associated with neuropsychological development problems in late childhood.

Additional efficacy endpoints also include the incidence of grade III or IV severe ventricular hemorrhage (IVH) to postconceptional age (PCA) 40 weeks [specified time interval: baseline to PCA 40 weeks].

Incidence of bronchopulmonary dysplasia (BPD) at postconceptional age (PCA) 40 weeks [target time interval: PCA 40 weeks].

Incidence of chronic respiratory complication (CRM) or death before 6 months corrected age (CA) [specified time interval: from baseline to 6 months corrected age (CA)]. CRM is a common adverse complication arising from preterm birth, resulting in symptoms of recurrent respiratory disease that require the use of respiratory medications such as bronchodilators, the need for supplemental oxygen at home, frequent visits to the intensive care unit, or readmission to hospital, especially in the first year of life. CRM is measured by the use of medical resources to maintain the respiratory tract and by respiratory symptoms.

Functional status assessed by the Prematurity Infant Index (PREMII) at postconceptional age (PCA) 40 weeks [target time interval: PCA 36 weeks]. PREMII is a clinician-reported (ClinRO) data used to determine the overall functional maturity of neonates with extreme prematurity. The infant's functional status is determined by 8 key body functions (nutrition, weight gain, thermoregulation, assisted ventilation, apnea, bradycardia, desaturation events, and oxygen administration) that reflect the overall health and development of the infant.

Case Study 2: Prevention of BPD in Extreme Prematurity Infants.

A randomized trial of the effectiveness of IGF-1/IGFBP3 in preventing BPD was conducted with a parallel arm study. The study was conducted at multiple centers in Italy, the Netherlands, Poland, Sweden, the United Kingdom and the United States from June 18, 2010 to March 30, 2016.

The drug mecasermin rinfabate, which is an IGF-1/IGFBP3 drug, was administered via continuous intravenous infusion to subjects from study day 0 (birthday) until PMA 29 weeks + 6 days inclusive, when the subject's endogenous IGF-1 production is considered sufficient to maintain physiological serum IGF-1 levels. After discontinuation of clinical trial drug infusion, each subject was observed until PMA 40 weeks ± 4 days. This study is designed to determine the dose of rhIGF-8 044079

1/rhIGFBP-3 administered by continuous infusion (CI) is necessary to establish and maintain long-term serum IGF-1 levels within physiological limits in preterm infants to prevent retinopathy of prematurity. This study was a phase 2, randomized, controlled, assessor-blind study designed to confirm the dose, pharmacokinetics, safety and efficacy of rhIGF-1/rhIGFBP-3. 61 participants received insulin-like growth factor (rhIGF-I)/insulin-like growth factor binding protein-3 (rhIGFBP-3) at a dose of 250 micrograms per kilogram (mcg/kg) over 24 hours via continuous intravenous (IV) /c) infusions from day 0 to postconceptional age (PCA) 29 weeks and 6 days. As a control group, 60 participants received standard therapy only. In table Figure 1 illustrates the distribution of participants in the overall study.

Table 1

Distribution of participants: general results of the study

rhIGF-l/rhIGFBP-3 Standard therapy (control) STARTED 61 60 COMPLETED 46 46 NOT COMPLETED 15 14 Termination of participation by initiative of the subject 2 1 Adverse event AND 9 Deviation from the protocol 2 2 Administrative decision 0 1 Other unspecified 0 1

In table Figure 2 shows the group that participated in the study.

table 2

rhIGF-l/rhIGFBP-3 Standard therapy (control) Total Total analyzed participants [units: participants] 61 60 121 Age [units: weeks] mean (standard deviation) 25.60 (1.207) 25.62 (1.397) 25.61 (1,300) Gender: female, male [units: participants] number of participants Female 22 36.1% 21 35.0% 43 35.5% Male 39 63.9% 39 65.0% 78 64.5%

Additional performance criteria throughout the study included, but were not limited to, the following:

time of discharge from neonatal intensive care unit (TDNIC) [specified time interval: day 0 to 40 weeks postconceptional age (EOS)].

Number of participants with bronchopulmonary dysplasia (BPD) [time point: at postconceptional age 36 weeks].

BPD severity as moderate, moderate, and severe was defined based on National Institute of Child Health and Human Development (NICHD) guidelines in preterm infants born at a gestational age (GA) of less than (<) 32 weeks.

Moderate: Oxygen requirement for first 28 days but on room air at RMA at 36 weeks or discharge to home care, whichever comes first.

Average BPD: Oxygen requirement for the first 28 days and <30 percent (%) oxygen at PMA 36 weeks or discharge to home care, whichever comes first.

Severe BPD: oxygen requirement for the first 28 days and an amount of oxygen that is greater than or equal to (>) 30%, through a head hood or nasal cannula, or the creation of continuous positive airway pressure through mechanical ventilation or using a high-pressure nasal cannula flow rate >2 L/min in PMA 36 weeks, or discharge to home care, whichever comes first.

Rate of weight change [specified time interval: day 0 to 40 weeks postconceptional age (EOS)]. The rate of change represents the rate of change in the mass of a particular organism per day in kilograms (kg).

Rate of change in length [specified time interval: day 0 to postconceptional age 40 weeks (EOS)].

The rate of change represents the change in length per day in centimeters (cm). Number of participants with a treatment-emergent adverse event (TEAE) and a treatment-emergent serious adverse event (TESAE) [specified time interval: day 0 to 40 weeks EOS].

An adverse event (AE) was any adverse medical event in a participant who received a clinical trial drug, without regard to cause and effect. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes or was considered significant for any other reason: death; initial or extended hospitalization of the patient; life-threatening condition (immediate risk of death); persistent or significant disability/disability; congenital anomaly.

A treatment-emergent adverse event was defined as the occurrence of any AE or worsening in the severity of a pre-existing AE at any time on or after the date of the first dose of study product.

Percentage serum IGF-1 concentrations falling within the target range after rhIGF-1/rhIGFBP-3 infusion [target time interval: day 0 to postconceptional age 40 weeks (EOS)].

Serum samples were collected from treated participants and control participants for quantification of IGF-1 using validated immunoassays. The target range for serum IGF-1 was 28–109 μg/L. Serum IGF-1 levels were recorded as a percentage of treated participants that fell within the target range.

Serum IGFBP-3 concentrations following intravenous (IV) infusion of rhIGF-1/rhIGFBP-3 [specified time interval: day 0 to postconceptional age 40 weeks].

Serum acid labile subunit (ALS) concentrations following intravenous (IV) infusion of rhIGF-1/rhIGFBP-3 [time point: day 7 to postconceptional age 40 weeks].

In table Figure 3 illustrates the measured BPD values as an additional performance criterion.

Table 3

rhlGFl/rhIGFBP-3 Standard therapy (control) Number of participants analyzed [units: participants] 47 49 Number of participants with bronchopulmonary dysplasia (BPD) [units: participants] Without BPD 4 4 Moderate 23 16 Average 9 5 Heavy 10 22 Unable to determine 1 2

Statistical analysis of the number of participants with bronchopulmonary dysplasia (BPD) is not presented.

Although certain compounds, compositions and methods described herein have been specifically described in accordance with certain embodiments, the following examples serve only to illustrate the compounds of the present invention and are not intended to be limiting.

The singular forms used herein in the description and claims, unless expressly stated to the contrary, are to be understood to include references to the plural. Claims or specifications that include or between one or more members of a group are considered to satisfy the requirements if one, more than one, or all members of the group are present, used, or otherwise relate to the specified product or method, unless otherwise stated or otherwise obvious. from the context. The present invention includes embodiments in which exactly one member of the group is present, used or otherwise related to the specified product or method. The present invention also includes embodiments in which more than one or all members of the group are present, used or otherwise related to the specified product or method. It is further understood that the present invention includes all variations, combinations and combinations in which one or more limitations, elements, conditions, descriptive terms, etc. from one or more of the listed claims are inserted into another claim, dependent on the same independent claim (or any other claim, as applicable), unless otherwise indicated or unless it would be apparent to one skilled in the art that a conflict or inconsistency would arise. If elements are presented in list form (eg, a Markush group or similar format), it should be understood that each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, it should be understood that if the present invention or aspects of the present

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Claims (15)

inventions are intended to include specific elements, features, etc., then certain embodiments of the present invention or aspects of the present invention are or are substantially composed of such elements, features, etc. For the purpose of simplicity, such embodiments have not been identified in every case are set out in this document in detail and specifically. It should also be understood that any embodiment or aspect of the present invention may be expressly excluded from the claims regardless of whether a specific exclusion is set forth in the specification. Publications, web pages and other reference materials incorporated herein by reference to describe the background of the present invention and to provide additional information regarding its practice are incorporated herein by reference. CLAIM 1. A method of treating bronchopulmonary dysplasia, comprising administering, by continuous intravenous infusion, to a premature infant in need of treatment, a therapeutic composition containing recombinant insulin-like growth factor-1 (IGF-1) and recombinant insulin-like growth factor-binding protein-3 (IGFBP- 3), combined before administration, at a dose of 250 to 500 micrograms/kg/24 hours, from birth to postconceptional age (PCA) of 24 to 34 weeks. 2. The method of claim 1, wherein the infant was born at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months or 3 months premature. 3. The method according to claim 1 or 2, where IGF-1 is administered at a dose of 250, 300, 350, 400 or 500 micrograms/kg/24 hours. 4. Method according to any one of paragraphs. 1-3, where IGF-1 is administered at a dose of 250 micrograms/kg/24 hours. 5. Method according to any one of paragraphs. 1-3, where IGF-1 is administered at a dose of 400 micrograms/kg/24 hours. 6. The method according to any of the previous claims, wherein IGF-1 is administered from birth to PMA, which is from 28 to 32 weeks. 7. The method according to any of the previous paragraphs, wherein IGF-1 is administered from birth to PMA, which is 29 weeks plus 6 days. 8. The method of any one of the preceding claims, wherein the subject has reduced serum IGF-1 levels. 9. The method of claim 7, wherein the reduced serum IGF-1 levels are between 30 and 50 micrograms/L. 10. Method according to any one of paragraphs. 1-9, where IGF-1 and IGFBP-3 are complexed in equimolar amounts. 11. The method of any one of the preceding claims, wherein administration of IGF-1 results in a reduction in the incidence of chronic respiratory complication (CRM) to 12 months corrected age (CA). 12. The method of any one of the preceding claims, wherein administration of IGF-1 results in a reduction in the incidence of bronchopulmonary dysplasia (BPD) to a postconception age (PCA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months. 13. The method of any one of the preceding claims, wherein administration of IGF-1 results in a reduction in the incidence of grade III or IV severe ventricular hemorrhage (IVH) up to postconceptional age (PCA) of 36 weeks, 40 weeks, 6 months , 8 months, 10 months or 12 months. 14. A method of reducing the incidence of retinopathy of prematurity (ROP) to a postconceptional age (PCA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months or 12 months, comprising administering a therapeutic composition by continuous intravenous infusion to a preterm infant in need of treatment. containing recombinant insulin-like growth factor-1 (IGF-1) and recombinant insulin-like growth factor binding protein-3 (IGFBP-3) complexed before administration at a dose of 250 to 500 micrograms/kg /24 hours, from birth to postconceptional age (PCA), which is 24 to 34 weeks. 15. A method of improving the functional status, as assessed by the Prematurity Infant Index (PREMII), to a postconceptional age (PCA) of 36 weeks, 40 weeks, 6 months, 8 months, 10 months or 12 months, involving administration by continuous intravenous infusion to a person in need of treating a premature infant with a therapeutic composition containing recombinant insulin-like growth factor-1 (IGF-1) and recombinant insulin-like growth factor binding protein 3 (IGFBP-3) complexed before administration at a dose of 250 to 500 microgram/kg/24 hours, from birth to postconceptional age (PCA) of 24 to 34 weeks. Kommersant Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 -