A long-acting growth hormone formulation with superior efficacy compared to daily somatropin.

Abstract

The present invention provides a pharmaceutical formulation for use in reducing the percentage of unresponsive individuals in a patient population suffering from growth hormone deficiency. [Solution] A long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, is provided.

Description

[Technical Field]

[0001] The present invention relates to a long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, for use in a method of treating growth hormone deficiency with improved outcomes. [Background technology]

[0002] Human growth hormone (hGH) is widely used to treat GH deficiency (GHD) or short stature resulting from GH deficiency, and other growth disorders. Currently, in most fields, growth hormone (GH) is only available in the form of daily injections.

[0003] Prescription practices for daily growth hormone preparations indicate that dosage should be individualized based on each patient's weight and growth response. Typical doses for children with growth hormone deficiency range from 0.17 mg / kg / week to 0.30 mg / kg / week.

[0004] Non-compliance with growth hormone therapy is widespread. Non-compliance with current hGH treatment is frequent because the drug needs to be injected daily over many years, and patients perceive daily injections as invasive. Non-compliance has a proven negative impact on treatment outcomes. Ease of use of the injection device, the characteristics of the injection device, and the frequency of injections can play a significant role in compliance.

[0005] To improve compliance and treatment outcomes, several companies are developing technologies to produce long-acting growth hormone products.

[0006] Nutropin Depot® was the first approved long-acting growth hormone, based on the encapsulation of growth hormone in biodegradable microparticles. Nutropin Depot was available on the U.S. market but was withdrawn in 2004.

[0007] Nutropin Depot was intended to be administered as a once-monthly or twice-monthly injection at a dose of 1.5 mg / kg / month or 0.75 mg / kg / month twice a month. In clinical studies, Nutropin Depot increased the annual height growth rate in children with growth hormone deficiency, but comparisons with historical studies showed that the growth rate achieved with daily treatment was faster than that achieved with Nutropin Depot.

[0008] Somatropin Biopartners was approved by the European Medicines Agency, but was subsequently withdrawn from use in the European Union. Somatropin Biopartners is a long-acting growth hormone based on the encapsulation of growth hormone in biodegradable microparticles. Somatropin Biopartners is prescribed for weekly administration. Clinical trials demonstrated that administration of 0.5 mg / kg / week to pediatric patients with growth hormone deficiency resulted in height growth rates equivalent to a daily growth hormone dose of 0.21 mg / kg / week, administered as a daily injection for 7 days.

[0009] None of the approved long-acting growth hormone preparations demonstrated superior efficacy compared to equimolar doses of somatropin daily. In addition to the two long-acting growth hormone preparations approved in Western countries, several other long-acting growth hormone preparations are under development.

[0010] For example, VRS-317 was studied in a phase 3 clinical trial in pediatric GHD patients. Patients treated with somavaratan twice monthly were found to have an annualized height growth rate (AHV) of 9.44 cm, compared to 10.7 cm in patients treated with genotropin daily. These results indicated that the trial did not meet the primary endpoint of non-inferiority for the primary efficacy variable, annual height growth rate, compared to daily growth hormone genotropin administered at 0.24 mg / kg / week.

[0011] Somatogon (MOD-4023, hGH-CTP) is administered in a Phase 2 dose-range study in pediatric GHD patients using a weekly dose regimen. Specifically, patients were administered doses of 0.25 mg / kg / week, 0.48 mg / kg / week, or 0.66 mg / kg / week. The 0.66 mg / kg / week dose is expected to produce efficacy equivalent to daily growth hormone and has been selected for further study in a Phase 3 clinical trial comparing its efficacy with daily somatropin administered at 0.24 mg / kg / week.

[0012] TV-1106 (albutropin) is being studied in a Phase 2 dose-range study in pediatric GHD patients using a fixed weekly dose regimen. Specifically, patients were administered a fixed dose of 0.554 mg / kg / week, 0.924 mg / kg / week, or 1.20 mg / kg / week. Neutralizing antibodies against TV-1106 have been detected, and development of TV-1106 has been discontinued.

[0013] Somapititan (NNC0195-0092) has been studied in dose-range studies in children with growth hormone deficiency. The study compared three somapititan doses (0.04, 0.08, or 0.16 mg / kg / week) with daily somatropin at 0.24 mg / kg / week. Annualized height growth rates were not significantly different at the 0.08 and 0.16 mg / kg / week doses compared to daily somatropin, but were inferior at lower doses. The mean annualized height growth rates for the three somapititan dose levels were 8.0 cm, 10.9 cm, and 12.9 cm, respectively, with the two highest doses being comparable to 11.4 cm for daily somatropin. [Overview of the Initiative] [Problems that the invention aims to solve]

[0014] None of the long-acting growth hormones currently in clinical development demonstrated superior efficacy compared to equimolar doses of daily somatropin. Furthermore, some failed to demonstrate equivalent efficacy to daily somatropin in Phase 3 clinical trials.

[0015] Furthermore, growth hormone treatment also presents a certain percentage of unresponsive individuals, i.e., patients who do not respond to a significantly increased amount of AHV compared to patients who do not receive growth hormone treatment, which is unsatisfactory for these patients. Therefore, it is necessary to reduce the number of unresponsive individuals.

[0016] In summary, despite several attempts, a long-acting growth hormone that shows superior efficacy compared to daily somatropin has not yet been developed. A long-acting growth hormone that increases the percentage of responding individuals and offers superior efficacy to daily somatropin is needed, which could help patients requiring growth hormone therapy to achieve the best therapeutic outcomes. [Means for solving the problem]

[0017] Therefore, an object of the present invention is to overcome the above-mentioned drawbacks at least partially.

[0018] This objective is achieved by a long-acting growth hormone, or a pharmaceutical formulation containing a long-acting growth hormone, wherein administration of the long-acting growth hormone or pharmaceutical formulation to patients with growth hormone deficiency yields superior efficacy compared to the administration of equimolar amounts of somatropin daily. [Modes for carrying out the invention]

[0019] In another aspect, the present invention relates to a long-acting growth hormone, or a pharmaceutical composition comprising a long-acting growth hormone, for use in a method of treating growth hormone deficiency with superior efficacy.

[0020] In another embodiment, the present invention relates to a method for treating a patient suffering from growth hormone deficiency, comprising the step of administering to the patient an effective amount of long-acting growth hormone or a pharmaceutical composition comprising such long-acting growth hormone, wherein the method of treatment yields excellent efficacy.

[0021] In another embodiment, the present invention relates to a long-acting growth hormone or a pharmaceutical formulation containing a long-acting growth hormone, wherein the long-acting growth hormone or pharmaceutical formulation contains a dose of 0.24 mg / kg / week of growth hormone or an equivalent amount of growth hormone, and administration of the long-acting growth hormone formulation to patients with growth hormone deficiency yields superior efficacy compared to the administration of a daily dose of 0.24 mg / kg / week of somatropin.

[0022] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical formulation containing a long-acting growth hormone for use in a method of treatment, wherein the long-acting growth hormone or pharmaceutical formulation is administered at a dose of 0.24 mg / kg / week of growth hormone or an equivalent amount of growth hormone, and the administration of the long-acting growth hormone or the pharmaceutical composition containing the long-acting growth hormone yields superior efficacy compared to the administration of a daily dose of 0.24 mg / kg / week of somatropin.

[0023] In another embodiment, the present invention relates to a method for treating a patient suffering from growth hormone deficiency, comprising the step of administering a long-acting growth hormone or a pharmaceutical preparation containing long-acting growth hormone in a dose of 0.24 mg / kg / week of growth hormone or a dose equivalent to growth hormone, wherein such treatment yields superior efficacy compared to the administration of a daily dose of somatropin at 0.24 mg / kg / week.

[0024] The phrase "a daily dose of somatropin of 0.24 mg / kg / week" is understood to mean that the cumulative daily dose of somatropin after one week of administration is 0.24 mg / kg, and that the daily dose of somatropin of such a daily dose is (0.24 mg / kg / week) / (7 days / week) = 0.343 mg / day (approximately).

[0025] In another embodiment, the present invention relates to a long-acting growth hormone, or a pharmaceutical formulation comprising such a long-acting growth hormone, for use in the treatment of growth hormone deficiency, wherein the treatment increases plasma IGF-1 levels by a standard deviation score (SDS) at least 0.2 greater than that of an equivalent daily dose of hGH.

[0026] In another aspect, the present invention relates to a method for treating growth hormone deficiency, comprising the step of administering an effective amount of long-acting growth hormone or a pharmaceutical composition comprising such long-acting growth hormone to a patient in need thereof, wherein the treatment for growth hormone deficiency increases plasma IGF-1 levels by SDS at least 0.2 more than an equivalent daily dose of hGH.

[0027] It is understood that SDS may be calculated at the patient population level, or for individual patients, by comparing the patient data with data from each patient population available in the literature. In one embodiment, the increase is at least 0.25 SDS. In one embodiment, the increase is at least 0.3 SDS. In one embodiment, the increase is at least 0.35 SDS. In one embodiment, the increase is at least 0.4 SDS.

[0028] In another embodiment, the present invention relates to a long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, for use in a method for reducing the percentage of unresponsive individuals in a patient population suffering from growth hormone deficiency.

[0029] In another embodiment, the present invention relates to a method for reducing the percentage of unresponsive individuals in a patient population suffering from growth hormone deficiency, comprising the step of administering an effective amount of the long-acting growth hormone of the present invention or a pharmaceutical formulation containing such long-acting growth hormone to patients in the patient population.

[0030] In one embodiment, the percentage of unresponsive individuals is reduced to less than 10%. In one embodiment, the percentage of unresponsive individuals is reduced to less than 9%. In one embodiment, the percentage of unresponsive individuals is reduced to less than 8%. In one embodiment, the percentage of unresponsive individuals is reduced to less than 7%. In one embodiment, the percentage of unresponsive individuals is reduced to less than 6%. In one embodiment, the percentage of unresponsive individuals is reduced to less than 5%. In one embodiment, the percentage of unresponsive individuals is reduced to less than 4%.

[0031] In another embodiment, the present invention relates to a long-acting growth hormone, or a pharmaceutical composition comprising such long-acting growth hormone, for use in a method for treating individuals unresponsive to growth hormone treatment. In other words, the present invention relates to a long-acting growth hormone, or a pharmaceutical composition comprising such long-acting growth hormone, for use in treating growth hormone deficiency in patients who are unresponsive individuals. In one embodiment, such unresponsive individuals have previously been treated with daily growth hormone.

[0032] In another embodiment, the present invention relates to a method for treating growth hormone deficiency in an unresponsive individual, comprising the step of administering an effective amount of long-acting growth hormone or a pharmaceutical composition containing such long-acting growth hormone to a patient in need. In one embodiment, such patient is a patient who has previously been treated with daily growth hormone.

[0033] In another embodiment, the present invention relates to a long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, for use in a method for increasing the percentage of responsive individuals in a patient population suffering from growth hormone deficiency.

[0034] In another embodiment, the present invention relates to a method for increasing the percentage of responding individuals in a patient population suffering from growth hormone deficiency, comprising the step of administering an effective amount of long-acting growth hormone or a pharmaceutical composition containing such long-acting growth hormone to patients in the patient population.

[0035] In one embodiment, the percentage of responding individuals is increased to at least 90%. In one embodiment, the percentage of responding individuals is increased to at least 91%. In one embodiment, the percentage of responding individuals is increased to at least 92%. In one embodiment, the percentage of responding individuals is increased to at least 93%. In one embodiment, the percentage of non-responding individuals is increased to at least 94%. In one embodiment, the percentage of non-responding individuals is increased to at least 95%. In one embodiment, the percentage of non-responding individuals is increased to at least 96%.

[0036] Surprisingly, equimolar administration of long-acting growth hormone was found to provide a better annual height growth rate (AHV) than daily somatropin.

[0037] Surprisingly, providing long-acting growth hormone with a PK profile that offers sustained exposure throughout the course of administration frequency was found to be associated with superior AHV.

[0038] The PK profile of hGH released from TransCon hGH may lead to improved growth hormone receptor association in target tissues, which is hypothesized to result in higher AHV and IGF-1 levels compared to the same daily dose of hGH.

[0039] Superior AHV can be explained by the delivery pattern of hGH to peripheral tissues after sustained hGH release from long-acting growth hormone, compared to intermittent exposure after daily hGH administration.

[0040] The pharmacodynamic effects of intermittent versus continuous hGH exposure in target tissues have been studied in healthy adults, where hGH was delivered by continuous infusion or pulsatile delivery. Human growth hormone infusion was approximately twice as effective in increasing both plasma IGF-I concentration and IGF-I mRNA in muscle compared to pulsatile GH exposure (Surya et al., J Clin Endocrinol Metab 94: 2828-2834, 2009). These data are supported by studies in growth hormone-deficient adults, where continuous GH infusions were associated with significantly higher IGF-1 levels compared to bolus injections at equivalent daily doses (Jorgensen et al., The Journal of Clinical Endocrinology & Metabolism, Volume 70, Issue 6, 1 June 1990, Pages 1616-1623; Laursen et al., J Clin Endocrinol Metab 86:1222-1228, 2001). However, no differences in clinical outcomes were observed in this study.

[0041] Administration of long-acting growth hormone with a PK profile that provides sustained exposure throughout the course of administration frequency was surprisingly associated with superior AHV. Previously, Nutropin Depot, a long-acting growth hormone based on PLGA encapsulation of growth hormone, failed to demonstrate superior treatment outcomes in children with GHD. In fact, compared to historical controls, the growth rate achieved with daily growth hormone treatment was faster than that achieved with Nutropin Depot. In addition, when patients receiving daily growth hormone treatment were switched to Nutropin Depot, they experienced a decrease in growth rate, which was on a larger scale than what might be considered a normal decrease experienced by patients remaining on daily growth hormone treatment. The PK profile of Nutropin Depot may not have been optimized because approximately 50-60% of GH exposure occurred during the first two days, and growth hormone levels had returned to baseline before the next injection (J Clin Endocrinol Metab, October 2001, 86(10):4700-4706; J Clin Endocrinol Metab, July 2004, 89(7):3234-3240).

[0042] It was also surprising to find that equimolar administration of long-acting growth hormone could reduce the proportion of unresponsive individuals compared to daily somatropin administration.

[0043] Within the scope of this invention, terms are used with the following meanings:

[0044] As used herein, the term “human growth hormone (hGH)” refers to all hGH polypeptides, preferably derived from mammalian species, more preferably from humans and mammalian species, more preferably from humans and murid species, as well as their variants, analogs, orthologues, homologs and derivatives, and their fragments, characterized by promoting growth during the growth period and maintaining normal body composition, anabolism and lipid metabolism. Preferably, the term “hGH” refers to the hGH polypeptide of SEQ ID NO: 1, and its variants, homologs and derivatives that exhibit essentially the same biological activity, i.e., promote growth during the growth period and maintain normal body composition, anabolism and lipid metabolism. More preferably, the term “hGH” refers to the polypeptide of SEQ ID NO: 1.

[0045] Sequence ID 1 has the following sequence: TIFF2026113655000001.tif26163

[0046] As used herein, the term "somatropin" refers to a polypeptide having the sequence of SEQ ID NO: 1.

[0047] As used herein, the term “hGH polypeptide variant” refers to a polypeptide that originates from the same species but is different from the reference hGH polypeptide. Preferably, such a reference hGH polypeptide sequence is the sequence of SEQ ID NO: 1. Generally, the differences are limited, and therefore the amino acid sequences of the reference and the variant are very similar as a whole and identical in many regions. Preferably, the hGH polypeptide variant is identical to the reference hGH polypeptide, preferably the hGH polypeptide of SEQ ID NO: 1, by at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%. A polypeptide having an amino acid sequence that is at least, for example, 95% “identical” to the amino acid sequence of the query is intended to mean that the amino acid sequence of the target polypeptide is identical to that of the query sequence, except that the sequence of the target polypeptide may contain up to 5 amino acid modifications per 100 amino acids of the amino acid sequence of the query. Such modifications to the reference sequence may occur at the amino (N-terminal) or carboxyl (C-terminal) positions of the reference amino acid sequence, or anywhere between those terminal positions, either individually scattered between residues in the reference sequence or scattered within one or more contiguous groups in the reference sequence. The query sequence may be the entire amino acid sequence of the reference sequence or any fragment as specified herein. Preferably, the query sequence is the sequence of Sequence ID No. 1.

[0048] Such hGH polypeptide variants may be isoforms encoded by native variants, such as native allele variants encoded by one of several alternative forms of hGH occupying a given locus of a chromosome or organism, or by native splice variants derived from a single primary transcript. Alternatively, hGH polypeptide variants may be variants not known to occur naturally and that can be produced using mutagenesis techniques known in the art.

[0049] It is known in this field that one or more amino acids can be deleted from the N-terminus or C-terminus of a biologically active peptide or protein without substantially losing its biological function.

[0050] It is also recognized by those skilled in the art that the amino acid sequence of a portion of an hGH polypeptide can be altered without significantly affecting the structure or function of the protein. Such mutations include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art to have little effect on activity. For example, guidance on how to perform silent amino acid substitutions phenotypically is presented in Bowie et al. (1990), Science 247:1306-1310, which is incorporated herein by reference in its entirety, in which the authors show that there are two main approaches to studying tolerance to changes in amino acid sequence.

[0051] The term hGH polypeptide also encompasses all hGH polypeptides encoded by hGH analogs, orthologs, and / or species homologs. As used herein, the term “hGH analog” refers to hGH from different, unrelated organisms that perform the same function in each organism but do not originate from an ancestral structure common to the ancestors of those organisms. Instead, similar hGHs arose independently and then subsequently evolved to perform the same or similar functions. In other words, similar hGH polypeptides are polypeptides that have entirely different amino acid sequences but exhibit the same biological activity, i.e., polypeptides that promote growth during the growth period and maintain normal body composition, anabolism, and lipid metabolism.

[0052] As used herein, the term “hGH ortholog” refers to two different hGHs within different species whose sequences are related to each other via a common, homogeneous hGH in an ancestral species, but have evolved to become distinct from each other.

[0053] As used herein, the term “hGH homolog” refers to hGH from different organisms that perform the same function in each organism and originate from an ancestral structure common to the ancestors of those organisms. In other words, homogeneous hGH polypeptides are polypeptides that exhibit the same biological activity and have completely similar amino acid sequences, i.e., polypeptides that promote growth during the growth period and maintain normal body composition, anabolism, and lipid metabolism. Preferably, an hGH polypeptide homolog can be defined as a polypeptide that exhibits at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity with a reference hGH polypeptide, preferably the hGH polypeptide of SEQ ID NO: 1.

[0054] Accordingly, the hGH polypeptide according to the present invention may, for example, be: (i) in which at least one of the amino acid residues is substituted with a conserved amino acid residue or a non-conserved amino acid residue, preferably a conserved amino acid residue, such that the substituted amino acid residue may or may not be encoded by the gene code; and / or (ii) in which at least one of the amino acid residues contains a substituent; and / or (iii) in which the hGH polypeptide is fused with another compound, for example, a compound that increases the half-life of the polypeptide (e.g., polyethylene glycol); and / or (iv) in which further amino acids are fused with the hGH polypeptide, for example, an IgG Fc fusion region peptide, or a leader sequence or secretion sequence, or a sequence used for the purification of the polypeptide in the above forms, or a preprotein sequence.

[0055] The hGH polypeptide may be a monomer or a multimer. The multimer may be a dimer, trimer, tetramer, or a multimer comprising at least five monomeric polypeptide units. The multimer may also be a homodimer or a heterodimer. The multimer of the present invention may be the result of hydrophobic association, hydrophilic association, ionic association and / or covalent association, and / or may be indirectly linked, for example, by the formation of liposomes. Preferably, the hGH polypeptide is a monomer.

[0056] As used herein, the term “hGH polypeptide fragment” means any peptide or polypeptide comprising a contiguous span of a portion of the amino acid sequence of an hGH polypeptide, preferably the polypeptide of SEQ ID NO: 1.

[0057] More specifically, an hGH polypeptide fragment contains at least 6, preferably at least 8 or 10, more preferably at least 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 125, 150, 175, or 191 consecutive amino acids of the hGH polypeptide, more preferably the polypeptide of SEQ ID NO: 1. An hGH polypeptide fragment can be further described as a subgenus of an hGH polypeptide containing at least 6 amino acids, where “at least 6” is defined as any integer between 6 and an integer representing the C-terminal amino acid of the hGH polypeptide, preferably the polypeptide of SEQ ID NO: 1. Further species of hGH polypeptide fragments having a length of at least 6 amino acids as described above, as further specified with respect to the N-terminal and C-terminal positions, are included. Similarly, all hGH polypeptide fragments having a length of at least 6 amino acids as described above, as can be specified in particular by the N-terminal and C-terminal positions, are encompassed by the term “hGH polypeptide fragment” as individual species. In other words, with respect to a given arbitrary amino acid sequence of an hGH polypeptide, preferably the hGH polypeptide of SEQ ID NO: 1, each combination of the N-terminal and C-terminal positions that can be occupied by a fragment having a length of at least six consecutive amino acid residues is included in the present invention.

[0058] It should be noted that the above species of polypeptide fragments can alternatively be described by formulas "a to b". In this case, "a" is equal to the position of most of the amino acids at the N-terminus of the polynucleotide, and "b" is equal to the position of most of the amino acids at the C-terminus. Furthermore, "a" is equal to an integer between 1 and the number of amino acids in the hGH polypeptide sequence minus 6, and "b" is equal to an integer between 7 and the number of amino acids in the hGH polypeptide sequence. Preferably, "a" is an integer smaller than "b" by at least 6 of the hGH polypeptide sequence of SEQ ID NO: 1.

[0059] As used herein, the terms “long-acting growth hormone” or “long-acting growth hormone compound” refer to a compound containing hGH in a crystalline form, or a compound containing hGH in which hGH is embedded, fused, or conjugated with at least one other compound or moiety, such as a polymer or fatty acid-derived moiety, and which has an increased retention time in the patient’s body compared to unmodified hGH. Retention time is the time between two consecutive doses in which the plasma concentration of unmodified hGH, e.g., SEQ ID NO: 1 or SEQ ID NO: 2, is at a therapeutically effective concentration. In some embodiments, such a therapeutically effective level is a plasma concentration of at least 2 ng hGH / ml. With respect to hGH, the retention time is approximately 12 hours. In some embodiments, the retention time of the long-acting growth hormone is at least 24 hours. In some embodiments, the retention time of the long-acting growth hormone is at least 36 hours. In some embodiments, the retention time of the long-acting growth hormone is at least 48 hours. In some embodiments, the retention time of the long-acting growth hormone is at least 72 hours.

[0060] It is also understood that the time between two consecutive doses of long-acting growth hormone is increased compared to standard treatment with once-daily hGH. In some embodiments, the time between two consecutive doses is at least two days. In some embodiments, the time between two consecutive doses is at least three days. In some embodiments, the time between two consecutive doses is at least four days. In some embodiments, the time between two consecutive doses is at least five days. In some embodiments, the time between two consecutive doses is at least six days. In some embodiments, the time between two consecutive doses is one week. In some embodiments, the time between two consecutive doses is two weeks. In some embodiments, the time between two consecutive doses is four weeks.

[0061] In one embodiment, the dose administered in each administration is at least 0.16 mg / kg / week. In another embodiment, the dose is in the range of 0.16 mg / kg / week to 0.4 mg / kg / week, for example, 0.24 mg / kg / week to 0.3 mg / kg / week. In another embodiment, the dose is 0.24 mg / kg / week. In yet another embodiment, the dose is 0.3 mg / kg / week.

[0062] In one embodiment, a therapeutically effective concentration is achieved for at least 50% of the dosing interval, i.e., a therapeutically effective concentration is achieved for at least 50% of the period between two consecutive administrations of long-acting growth hormone.

[0063] As used herein, the term “drug” means a substance used in the treatment, cure, prevention or diagnosis of a disease, or otherwise used to enhance the physical or mental health of a patient. If a drug is conjugated to another part, the resulting product derived from the drug is referred to as the “drug part” or “bioactive part.”

[0064] As used herein, the term “prodrug” refers to a bioactive moiety that is reversibly and covalently bound to a specific protecting group via a reversible prodrug linker moiety containing a reversible linking group to the bioactive moiety, in order to modify or eliminate undesirable properties in the parent molecule. This includes enhancing desired properties and suppressing undesirable properties in the drug. The specific non-toxic protecting group is called a “carrier.” The prodrug releases the reversibly and covalently bound bioactive moiety in the form of its corresponding drug.

[0065] As used herein, the terms "growth hormone equivalent" and "hGH equivalent" refer to the total mass of hGH or hGH moiety contained in a long-acting growth hormone compound. In other words, if the long-acting growth hormone compound is a prodrug in which, for example, the hGH moiety is reversibly conjugated to a polymer, the term "growth hormone equivalent" refers to the total mass of the hGH moiety, but not the total mass of the hGH prodrug. If the long-acting growth hormone compound is a fusion protein in which, for example, the hGH moiety is fused to a natural or unnatural amino acid sequence, the term "growth hormone equivalent" refers to the total mass of the hGH moiety, but not the total mass of the fusion protein.

[0066] As used herein, the term “equomole” means having the same number of moles.

[0067] The terms “formulation,” “pharmaceutical formulation,” “composition,” and “pharmaceutical composition” are used synonymously and refer to a combination of one or more long-acting hGHs, one or more excipients, and any combination of any two or more components of the composition, any product obtained directly or indirectly as a result of complex formation or aggregation, or as a result of dissociation of one or more components, or as a result of other types of reactions or interactions of one or more components. In some embodiments, the terms “formulation,” “pharmaceutical formulation,” “composition,” and “pharmaceutical composition” refer to at least one long-acting hGH and at least one excipient.

[0068] As used herein, the term “liquid formulation” means a formulation comprising a long-acting hGH and at least one solvent. The preferred solvent is water.

[0069] As used herein, the term “dried formulation” means that the long-acting growth hormone is provided in a dried form. Preferred drying methods are spray drying and freeze-drying, also known as lyophilization. Such dried formulations have a residual water content of up to 10%, preferably less than 5%, and more preferably less than 2%, as determined in accordance with Karl Fischer. The preferred drying method is freeze-drying. “Lyophilized formulation” means that the dried formulation has been first frozen and subsequently subjected to a reduction in moisture by a vacuum means. This technical term does not exclude additional drying steps that can be performed in the manufacturing method before filling the formulation into the final container.

[0070] As used herein, the term “reconstituted formulation” refers to the result of adding a solvent, also called a “reconstituted solution,” to a dry formulation. Preferably, the amount of solvent is such that the dry formulation is completely dissolved in the resulting reconstituted formulation.

[0071] As used herein, the term “superior” refers to a statistically significantly better treatment outcome, for example, with respect to AHV. In some embodiments, “statistically significantly better” is defined as a p-value less than 0.05, e.g., less than 0.01, using a preferred statistical model. In some embodiments, such a statistical model is analysis of variance (ANOVA). In some embodiments, such a statistical model is analysis of covariance (ANCOVA).

[0072] As used herein, the term “unit dose” refers to the amount of drug, particularly long-acting growth hormone preparations, that constitutes one dose, i.e., one administration.

[0073] As used herein, the term “unit dosage form” refers to the presentation of a unit dose, i.e., any administration device containing a unit dose of a drug, particularly a long-acting growth hormone preparation. Preferred administration devices are selected from the group consisting of needle syringes, injection pens, auto-injector pens, needleless syringes, electronic syringes, and dual-chamber cartridges.

[0074] As used herein, the term “potency” refers to both the annualized height growth rate achieved in children with naive growth hormone and the percentage of individuals that respond.

[0075] As used herein, "pharmaceutical effective dose" refers to an amount of growth hormone or growth hormone equivalent sufficient to treat growth hormone deficiency.

[0076] As used herein, the term “responsive individual” refers to a growth hormone-deficient patient who is receiving growth hormone therapy and has an annualized height growth rate greater than 8.0 cm per year.

[0077] As used herein, the term “unresponsive individual” refers to a growth hormone-deficient patient receiving growth hormone therapy and having an annualized height growth rate of less than 8.0 cm per year. The growth hormone therapy is understood to be standard treatment with human growth hormone, for example, in one embodiment, daily administration of human growth hormone SEQ ID NO: 1 at doses ranging from 0.17 mg / kg / week to 0.30 mg / kg / week. Exemplary doses are hGH SEQ ID NO: 1 at 0.24 mg / kg / week and 0.3 mg / kg / week.

[0078] As used herein, the term “annualized height growth rate” or “annual height growth rate” (“AHV”) is defined as the difference in height between the start of treatment and approximately 12 months later.

[0079] As used herein, the term “about” in combination with a number is used to indicate not only the number itself, but also a range of plus or minus 10%, more preferably 8%, even more preferably 5%, and most preferably 2%. For example, the phrase “about 20%” is used to mean not only 20% itself, but also a range of 20%+ / -10%, preferably 20%+ / -8%, even more preferably 20%+ / -5%, and most preferably 20%+ / -2%.

[0080] As used herein, the term “excipient” refers to a diluent, adjuvant, or vehicle administered together with a therapeutic agent.

[0081] As used herein, the term “hydrogel” means a hydrophilic or amphiphilic polymer network structure composed of homopolymers or copolymers that are insoluble due to the presence of covalent chemical crosslinking. This crosslinking results in a network structure and physical integrity. Hydrogels exhibit thermodynamic compatibility with water, which causes them to swell in aqueous media.

[0082] As used herein, the term “functional group” means a group of atoms that can react with other functional groups. Functional groups include, but are not limited to, the following groups: carboxylic acids (-(C=O)OH), primary or secondary amines (-NH2, -NH-), maleimides, thiols (-SH), sulfonic acids (-(O=S=O)OH), carbonates, carbamates (-O(C=O)N<), hydroxy(-OH), aldehydes (-(C=O)H), ketones (-(C=O)-), hydrazines (>NN<), isocyanates, isothiocyanates, phosphoric acids (-O(P=O)OHOH), phosphonic acids (-O(P=O)OHH), haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziridines.

[0083] As used herein, the term “part” means a portion of a molecule that lacks at least one atom compared to the corresponding reagent. For example, when a reagent of the formula “HXH” reacts with another reagent and becomes part of a reaction product, the corresponding part of this reaction product has the structure “HX-” or “-X-”, where each “-” indicates a bond to another part. Thus, the biologically active part is released from the prodrug as a drug.

[0084] When an arrangement or chemical structure of an atomic group is presented, and that atomic group is bonded to two parts or interrupts a part, it is understood that, unless otherwise explicitly stated, the arrangement or chemical structure can bond to these two parts in either direction. For example, part "-C(O)N(R)-" can bond to two parts as either "-C(O)N(R)-" or "-N(R)C(O)-", or interrupt a part. Similarly, part

[0085] [ka] teeth,

[0086] [ka] or

[0087] [ka] It can be either combined into two parts, or one part can be interrupted.

[0088] If the long-acting growth hormone contains one or more acidic or basic groups, the present invention also includes corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular pharmaceutically usable salts thereof. Thus, long-acting growth hormones containing acidic groups can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, or amino acids). Long-acting growth hormones containing one or more basic groups, i.e., protonable groups, can exist and can be used according to the present invention in the form of addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods for converting basic groups to cations, such as alkylation of amine groups, are known to those skilled in the art, resulting in suitable counterions for positively charged ammonium groups and their salts. When a long-acting growth hormone contains both acidic and basic groups in its molecule, the present invention also includes intramolecular salts or betaine (zwitterionic) in addition to the salt forms described. Each salt can be obtained by conventional methods known to those skilled in the art, such as by contacting them with an organic acid, inorganic acid, or base in a solvent or dispersion, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of long-acting growth hormone that are not directly suitable for use in pharmaceuticals due to their poor physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for preparing pharmaceutically acceptable salts.

[0089] The term "pharmaceutically acceptable" means that it has been approved for use in animals, preferably in humans, by a regulatory body, such as the EMA (Europe) and / or the FDA (United States), and / or any other national regulatory body.

[0090] As used herein, with respect to the binding of the first part to the second part, the terms “reversible,” “reversibly,” “degradable,” or “degradably” mean that the linking group connecting the first and second parts is cleavable under physiological conditions, which is an aqueous buffer solution at pH 7.4 and 37°C, and has a half-life in the range of 1 day to 1 month, for example, 2 days to 3 weeks, or for example, 3 days to 2 weeks. Therefore, with respect to the binding of the first part to the second part, the term “stable” means that the linking group connecting the first and second parts exhibits a half-life greater than 1 month under physiological conditions.

[0091] As used herein, the term "water-insoluble" refers to a compound that can dissolve in less than 1 g in 1 liter of water at 20°C to form a homogeneous solution. Conversely, the term "water-soluble" refers to a compound that can dissolve in 1 g or more in 1 liter of water at 20°C to form a homogeneous solution.

[0092] As used herein, the term “polymer” means a molecule containing monomers, which are repeating structural units linked by chemical bonds in a linear, cyclic, branched, crosslinked, or dendrimer form, or a combination thereof, and which may be of synthetic or biological origin, or a combination thereof. It is understood that polymers may also contain one or more other chemical groups and / or partials, for example, one or more functional groups. Preferably, soluble polymers have a molecular weight of at least 0.5 kDa, for example, at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, it is preferable that it has a molecular weight of at most 1000 kDa, for example, at most 750 kDa, for example, at most 500 kDa, for example, at most 300 kDa, for example, at most 200 kDa, for example, at most 100 kDa. It is understood that in the case of insoluble polymers, for example, crosslinked hydrogels, it is not possible to present a significant molecular weight range.

[0093] As used herein, the term “polymeric” means a reagent or portion comprising one or more polymers.

[0094] Those skilled in the art will understand that polymerization products obtained from polymerization reactions do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, as used herein, molecular weight range, molecular weight, range of monomer numbers in a polymer, and number of monomers in a polymer refer to the number-average molecular weight and the number average of monomers. As used herein, the term "number-average molecular weight" means the usual arithmetic mean of the molecular weights of individual polymers.

[0095] As used herein, the term "PEG-based containing at least X% PEG" in relation to a moiety or reagent means that said moiety or reagent contains at least X% (w / w) of ethylene glycol units (-CH2CH2O-), where in this case, the ethylene glycol units may be in block form, arranged alternately, or randomly distributed within said moiety or reagent, preferably, all of the ethylene glycol units of said moiety or reagent are present in one block, and the weight percentage of the remainder of the PEG-based moiety or reagent is preferably another moiety selected from the following moieties and linking groups: · C 1~50 alkyl, C 2~50 alkenyl, C 2~50 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and · a linking group selected from the group consisting of

[0096]

Chemical formula

[0097] The term "substituted", as used herein, means that one or more -H atoms of a molecule or moiety are replaced by different atoms or groups of atoms, referred to as "substituents".

[0098] Preferably, one or more additional optional substituents are halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(Rx1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 From the group consisting of alkinyls, -T 0 , C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R x2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3)C(O)N(R x3a )-, and -OC(O)N(R x3 )-; optionally interrupted by one or more groups selected from the group consisting of, R x1 , R x1a , R x1b is independently selected from the group consisting of -H, -T 0 , C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl, -T 0 , C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl may be optionally substituted by one or more identical or different R x2 s, C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O)2N(R x3 )-, -S(O)N(R x3 )-; -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-, -N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )-; optionally interrupted by one or more groups selected from the group consisting of, T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclic, T 0 is independently optionally substituted by one or more identical or different R x2 s, R x2 is each independently halogen, -CN, oxo (=O), -COORx4 、 -OR x4 、 -C(O)R x4 、 -C(O)N(R x4 R x4a 、 -S(O)2N(R x4 R x4a 、 -S(O)N(R x4 R x4a 、 -S(O)2R x4 、 -S(O)R x4 、 -N(R x4 、 -N(R x4a R x4b 、 -SR x4 、 -N(R x4 R x4a 、 -NO2, -OC(O)R x4 、 -N(R x4 、 -N(R x4a 、 -N(R x4 、 -N(R x4a 、 -N(R x4 、 -N(R x4a 、 -N(R x4 、 -N(R x4a 、 -N(R x4 、 -N(R x4a R x4b 、 -N(R x4 R x4a 、 and C 1~6 alkyl; independently selected from the group consisting of, C 1~6 alkyl is optionally substituted by one or more identical or different halogens, R x3 、R x3a 、R x4 、R x4a 、R x4b are each independently selected from the group consisting of -H and C 1~6 alkyl; independently selected from the group consisting of, C 1~6 alkyl is optionally substituted by one or more identical or different halogens.

[0099] More preferably, one or more additional optional substituents are halogen, -CN, -COOR x1 、 -OR x1 、 -C(O)R x1 、 -C(O)N(R x1 Rx1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 From the group consisting of alkinyls, -T 0 , C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 Alkinyl is one or more identical or different R x2 It is sometimes replaced by C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a)-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 It is optionally interrupted by one or more elements selected from the group consisting of )-; R x1 , R x1a , R x1b , R x3 , R x3a These are -H, halogen, and C respectively. 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkinyls, T 0 These are phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C, respectively. 3~10 Independently selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls, T 0 Each of these is independently one or more identical or different R x2 It is sometimes replaced by, R x2 These are halogen, -CN, oxo (=O), and -COOR, respectively. x4 , -OR x4 , -C(O)R x4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4)C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1~6 Independently selected from the group consisting of alkyl, C 1~6 Alkyl is optionally substituted with one or more identical or different halogens. R x4 , R x4a , R x4b These are -H, halogen, and C respectively. 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 It is independently selected from the group consisting of alkynnyls.

[0100] More preferably, one or more further optional substituents may be halogen, -CN, or -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 Rx1a ), -T 0 , C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 From the group consisting of alkinyls, -T 0 , C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is one or more identical or different R x2 It is sometimes replaced by C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 It is optionally interrupted by one or more elements selected from the group consisting of )-; R x1 , R x1a , R x1b , R x2 , R x3 , R x3a These are -H, halogen, and C respectively. 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Independently selected from the group consisting of alkinyls, T 0 These are phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C, respectively. 3~10 Independently selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls, T 0 Each of these is independently one or more identical or different R x2It is sometimes replaced by this.

[0101] Preferably, up to six -H atoms of the optionally substituted molecule or part are independently replaced by substituents, for example, five -H atoms are independently replaced by substituents, four -H atoms are independently replaced by substituents, three -H atoms are independently replaced by substituents, two -H atoms are independently replaced by substituents, or one -H atom is independently replaced by a substituent.

[0102] The term "spacer" as used herein refers to -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R z1 )-,-S(O)2N(R z1 )-,-S(O)N(R z1 )-, -S(O)2-, -S(O)-, -N(R z1 )S(O)2N(R z1a )-, -S-, -N(R z1 )-, -OC(OR z1 )(R z1a )-,-N(R z1 )C(O)N(R z1a )-,-OC(O)N(R z1 )-, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Preferably, this refers to a portion selected from the group consisting of alkynyl, -T-, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-,-S(O)2N(R z3 )-,-S(O)N(R z3 )-, -S(O)2-, -S(O)-, -N(R z3 )S(O)2N(R z3a)-, -S-, -N(R z3 )-, -OC(OR z3 )(R z3a )-,-N(R z3 )C(O)N(R z3a )-, and -OC(O)N(R z3 It is optionally interrupted by one or more elements selected from the group consisting of )-; R z1 and R z1a -H, -T, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Selected independently from the group consisting of alkynnyls, -T, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z4 )-,-S(O)2N(R z4 )-,-S(O)N(R z4 )-, -S(O)2-, -S(O)-, -N(R z4 )S(O)2N(R z4a )-, -S-, -N(R z4 )-, -OC(OR z4 )(R z4a )-,-N(R z4 )C(O)N(R z4a )-, and -OC(O)N(R z4 It is optionally interrupted by one or more elements selected from the group consisting of )-; T represents phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C respectively. 3~10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, T is independently selected from the group consisting of one or more identical or different R z2 It is sometimes replaced by, Rz2 These are halogen, -CN, oxo (=O), and -COOR, respectively. z5 , -OR z5 , -C(O)R z5 ,-C(O)N(R z5 R z5a ), -S(O)2N(R z5 R z5a ), -S(O)N(R z5 R z5a ), -S(O)2R z5 ,-S(O)R z5 , -N(R z5 )S(O)2N(R z5a R z5b ), -SR z5 , -N(R z5 R z5a ), -NO2, -OC(O)R z5 , -N(R z5 )C(O)R z5a , -N(R z5 )S(O)2R z5a , -N(R z5 )S(O)R z5a , -N(R z5 )C(O)OR z5a , -N(R z5 )C(O)N(R z5a R z5b ), -OC(O)N(R z5 R z5a ), and C 1~6 Independently selected from the group consisting of alkyl, C 1~6 Alkyl is optionally substituted with one or more identical or different halogens. R z3 , R z3a , R z4 , R z4a , R z5 , R z5a and R z5b These are -H and C, respectively. 1~6 Independently selected from the group consisting of alkyls, C 1~6 Alkyl atoms are optionally substituted with one or more identical or different halogens.

[0103] More preferably, the term "spacer" is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R z1 )-,-S(O)2N(R z1 )-,-S(O)N(R z1 )-, -S(O)2-, -S(O)-, -N(R z1 )S(O)2N(R z1a )-, -S-, -N(R z1 )-, -OC(OR z1 )(R z1a )-,-N(R z1 )C(O)N(R z1a )-,-OC(O)N(R z1 )-, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 This refers to a part selected from the group consisting of -T- and C. 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-,-S(O)2N(R z3 )-,-S(O)N(R z3 )-, -S(O)2-, -S(O)-, -N(R z3 )S(O)2N(R z3a )-, -S-, -N(R z3 )-, -OC(OR z3 )(R z3a )-,-N(R z3 )C(O)N(R z3a )-, and -OC(O)N(R z3 It is optionally interrupted by one or more elements selected from the group consisting of )-; R z1 and R z1a -H, -T, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Selected independently from the group consisting of alkynnyls, -T, C1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z4 )-,-S(O)2N(R z4 )-,-S(O)N(R z4 )-, -S(O)2-, -S(O)-, -N(R z4 )S(O)2N(R z4a )-, -S-, -N(R z4 )-, -OC(OR z4 )(R z4a )-,-N(R z4 )C(O)N(R z4a )-, and -OC(O)N(R z4 It is optionally interrupted by one or more elements selected from the group consisting of )-; T represents phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C respectively. 3~10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, T is independently selected from the group consisting of one or more identical or different R z2 It is sometimes replaced by, R z2 These are halogen, -CN, oxo (=O), and -COOR, respectively. z5 , -OR z5 , -C(O)R z5 ,-C(O)N(R z5 R z5a ), -S(O)2N(R z5 R z5a ), -S(O)N(R z5 R z5a ), -S(O)2R z5 ,-S(O)R z5 , -N(R z5 )S(O)2N(R z5a R z5b ), -SRz5 , -N(R z5 R z5a ), -NO2, -OC(O)R z5 , -N(R z5 )C(O)R z5a , -N(R z5 )S(O)2R z5a , -N(R z5 )S(O)R z5a , -N(R z5 )C(O)OR z5a , -N(R z5 )C(O)N(R z5a R z5b ), -OC(O)N(R z5 R z5a ), and C 1~6 Independently selected from the group consisting of alkyl, C 1~6 Alkyl is optionally substituted with one or more identical or different halogens. R z3 , R z3a , R z4 , R z4a , R z5 , R z5a and R z5b These are -H and C, respectively. 1~6 Independently selected from the group consisting of alkyls, C 1~6 Alkyl atoms are optionally substituted with one or more identical or different halogens.

[0104] More specifically, the term "spacer" is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R z1 )-,-S(O)2N(R z1 )-,-S(O)N(R z1 )-, -S(O)2-, -S(O)-, -N(R z1 )S(O)2N(R z1a )-, -S-, -N(R z1 )-, -OC(OR z1 )(R z1a )-,-N(R z1 )C(O)N(R z1a )-,-OC(O)N(R z1 )-, C 1~50 Alkyl, C 2~50 Alkenyl and C2~50 This refers to a part selected from the group consisting of -T- and C. 1~20 Alkyl, C 2~20 Alkenyl and C 2~20 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~20 Alkyl, C 2~20 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-,-S(O)2N(R z3 )-,-S(O)N(R z3 )-, -S(O)2-, -S(O)-, -N(R z3 )S(O)2N(R z3a )-, -S-, -N(R z3 )-, -OC(OR z3 )(R z3a )-,-N(R z3 )C(O)N(R z3a )-, and -OC(O)N(R z3 It is optionally interrupted by one or more elements selected from the group consisting of )-; R z1 and R z1a -H, -T, C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 Independently selected from the group consisting of alkinyls, T represents phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C respectively. 3~10 Independently selected from the group consisting of cycloalkyls, 3-10 membered heterocyclils, 8-11 membered heterobicyclils, 8-30 membered carbopolycyclils, and 8-30 membered heteropolycyclils, R z2 These are halogen and C, respectively. 1~6 Independently selected from the group consisting of alkyls, R z3 , R z3a , R z4 , R z4a , R z5 , R z5a and R z5b These are -H and C, respectively.1~6 From the group consisting of alkyls, C 1~6 Alkyl atoms are optionally substituted with one or more identical or different halogens.

[0105] The term “interrupted” means that a group of atoms is inserted into a portion between two carbon atoms, or, if this insertion is at one of the ends of that portion, between a carbon atom and a hydrogen atom. If a portion is interrupted by a group of atoms at one of its ends, and the interrupted portion is bonded to a second portion, it is understood that the interrupting group of atoms may also be positioned between the last atom of the first portion and the first atom of the second portion.

[0106] As used herein, the term "C 1~4 "Alkyl" refers to a linear or branched alkyl moiety, either alone or in combination, having 1 to 4 carbon atoms. When present at the end of a molecule, it refers to a linear or branched C 1~4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Two parts of the molecule are C 1~4 When linked by alkyl, such C 1~4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1~4 The hydrogen atoms of the alkyl carbons may be optionally replaced by substituents defined above. 1~4 The alkyl group may be interrupted by one or more parts as defined below.

[0107] As used herein, the term "C 1~6 "Alkyl" refers to a linear or branched alkyl moiety, either alone or in combination, having 1 to 6 carbon atoms. When present at the end of a molecule, it refers to linear and branched C atoms. 1~6Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. The two parts of the molecule are C 1~6 When linked by an alkyl group, such C 1~6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1~6 Each hydrogen atom of carbon may be optionally replaced by the substituents defined above. 1~6 The alkyl group may be interrupted by one or more parts as defined below.

[0108] Therefore, "C 1~10 Alkyl," "C 1~20 "Alkyl" or "C 1~50 "Alkyl" refers to an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively. 1~10 , C 1~20 or C 1~50 Each hydrogen atom of carbon may be optionally replaced by the substituents defined above. 1~10 Alkyl or C 1~50 The alkyl group may be interrupted by one or more parts as defined below.

[0109] As used herein, the term "C 2~6 An "alkenyl" refers to a straight-chain or branched hydrocarbon moiety that, alone or in combination, contains at least one carbon-carbon double bond having 2 to 6 carbon atoms. When present at the ends of a molecule, examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. Two parts of a molecule are C 2~6 When linked by an alkenyl group, such C2~6 An example of an alkenil is -CH=CH-. 2~6 Each hydrogen atom in the alkenyl moiety may be replaced by a substituent as defined above. 2~6 An alkenil may be interrupted by one or more parts as defined below.

[0110] Therefore, the term "C 2~10 Alkenil, "C 2~20 "Alkenil" or "C 2~50 "Alkenyl" means a linear or branched hydrocarbon moiety, either alone or in combination, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, and containing at least one carbon-carbon double bond. 2~10 Alkenil, C 2~20 Alkenyl or C 2~50 Each hydrogen atom of the alkenyl group may be optionally replaced by the substituents defined above. Optionally, C 2~10 Alkenil, C 2~20 Alkenyl or C 2~50 An alkenil may be interrupted by one or more parts as defined below.

[0111] As used herein, the term "C 2~6 "Alkynyl" refers to a linear or branched hydrocarbon moiety, either alone or in combination, that contains at least one carbon-carbon triple bond having 2 to 6 carbon atoms. When present at the end of a molecule, examples include -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of a molecule are linked by an alkynyl group, an example is -C≡C-. 2~6 Each hydrogen atom of the alkynyl group may be optionally replaced by the substituents defined above. Depending on the case, one or more double bonds may appear. Depending on the case, C 2~6 Alkinyl may be interrupted by one or more parts as defined below.

[0112] Therefore, when used herein, the term "C 2~10 Alkinyl, C 2~20 "Alkinyl" and "C 2~50 "Alkynyl" means a linear or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, each having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, either alone or in combination. 2~10 Alkinyl, C 2~20 Alkinyl or C 2~50 Each hydrogen atom of the alkynyl group may be optionally replaced by the substituents defined above. Depending on the case, one or more double bonds may appear. Depending on the case, C 2~10 Alkinyl, C 2~20 Alkinyl or C 2~50 Alkinyl may be interrupted by one or more parts as defined below.

[0113] As stated above, C 1~4 Alkyl, C 1~6 Alkyl, C 1~10 Alkyl, C 1~20 Alkyl, C 1~50 Alkyl, C 2~6 Alkenil, C 2~10 Alkenil, C 2~20 Alkenil, C 2~50 Alkenil, C 2~6 Alkinyl, C 2~10 Alkinyl, C 2~20 Alkenyl or C 2~50 Alkinyl is one or more of the following parts:

[0114] [ka] (In the formula, The dashed line indicates binding to the above portion or the rest of the reagent. R and R a (These are independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.) It may be interrupted depending on the circumstances.

[0115] As used herein, the term "C 3~10 "Cycloalkyl" refers to a cyclic alkyl chain having 3 to 10 carbon atoms, which can be saturated or unsaturated, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3~10 Each hydrogen atom of the cycloalkyl carbon may be replaced by the substituents defined above. 3~10 "Cycloalkyl" also includes cross-linked birings such as norbornane or norbornene.

[0116] The term "8-30 membered carbopolycyclyl" or "8-30 membered carbopoly ring" means a cyclic part consisting of two or more rings having 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and can contain up to the maximum number of double bonds (aromatic rings, or fully saturated, partially saturated, or unsaturated non-aromatic rings). Preferably, an 8-30 membered carbopolycyclyl means a cyclic part consisting of two, three, four, or five rings, more preferably two, three, or four rings.

[0117] As used herein, the terms “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” mean a ring (aromatic ring, or a fully saturated, partially saturated, or unsaturated non-aromatic ring) having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, which may contain up to the maximum number of double bonds, wherein at least one ring atom and up to four ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 3-10 member heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxilen, thiirane, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, This includes tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidined, isothiazolidine, thiadiazolidined, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidined, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3-10 membered heterocyclyl or 3-10 membered heterocyclic group may be replaced by a substituent as defined below.

[0118] As used herein, the terms “8- to 11-membered heterobicyryl” or “8- to 11-membered heterobicyclic” mean a heterocyclic portion of two rings having 8 to 11 ring atoms, wherein at least one ring atom is shared by both rings and may contain up to the maximum number of double bonds (an aromatic ring, or a fully saturated, partially saturated, or unsaturated non-aromatic ring), and at least one to up to six ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), which are linked to the rest of the molecule via carbon or nitrogen atoms. Examples of 8- to 11-membered heterobicyclic rings include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic ring also includes spiro structures of two rings, such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocyclic rings, such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of the carbon in an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicyclic ring may be replaced by substituents as defined below.

[0119] Similarly, the term “8-30 membered heteropolycyclyl” or “8-30 membered heteropolyring” means a heterocyclic portion of more than two rings, preferably three, four, or five rings, having 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and may contain up to the maximum number of double bonds (aromatic rings, or non-aromatic rings that are fully saturated, partially saturated, or unsaturated), and at least one to up to ten ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and this ring is linked to the rest of the molecule via carbon or nitrogen atoms.

[0120] As used herein, "halogen" means fluoro, chloro, bromo, or iodine. Generally, the halogen is preferably fluoro or chloro.

[0121] Generally, the terms "comprise" or "comprising" also include "consist of" or "consisting of."

[0122] According to the present invention, a long-acting growth hormone preparation is provided, and administration of the long-acting growth hormone preparation to patients with growth hormone deficiency yields superior efficacy compared to the administration of an equimolar dose of somatropin daily.

[0123] In one embodiment, a long-acting growth hormone, or a pharmaceutical composition containing the long-acting growth hormone, is administered using a syringe with a needle.

[0124] In another embodiment, a long-acting growth hormone, or a pharmaceutical composition containing the long-acting growth hormone, is administered using an injection pen.

[0125] In another embodiment, a long-acting growth hormone, or a pharmaceutical composition containing the long-acting growth hormone, is administered using an auto-injector pen.

[0126] In another embodiment, a long-acting growth hormone, or a pharmaceutical composition containing the long-acting growth hormone, is administered using a needleless syringe.

[0127] In another embodiment, a long-acting growth hormone, or a pharmaceutical composition containing the long-acting growth hormone, is administered using an electronic syringe.

[0128] In another embodiment, a long-acting growth hormone, or a pharmaceutical composition containing the long-acting growth hormone, is administered using a double-chamber cartridge, preferably a double-chamber cartridge loaded into a pen device or an electronic syringe.

[0129] In one embodiment, a long-acting growth hormone preparation, or a pharmaceutical composition containing the long-acting growth hormone, comprises growth hormone embedded or encapsulated in a matrix or vehicle containing a polymer or lipid.Preferred polymer matrices include 2-methacryloyloxyethylphosphoryl(phosphoyl)cholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), and poly(cyanoacrylates). Poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl methacrylates), poly(hydroxy(hydroxypropyl methacrylates)) Poly(oxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic acid-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyl oxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolides) The polymers include polymers selected from the group consisting of (sodium bicarbonates), silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0130] Preferred polymers are selected from the group consisting of PEG, polylactide-co-glycolide (PLGA), and hyaluronic acid. Most preferably, the polymer is PEG.

[0131] In one embodiment, the polymer matrix is ​​composed of 2-methacryloyloxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), and poly(cyanoacrylates). ), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl Oxazolines, poly(iminocarbonates), poly(lactic acids), poly(lactic acid-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones), silico This hydrogel contains polymers selected from the group consisting of celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon-based polymers, xylans, and copolymers thereof.

[0132] Preferred hydrogels contain polymers selected from the group consisting of PEG, polylactide-co-glycolide (PLGA), and hyaluronic acid. Most preferably, the hydrogel is a PEG-based hydrogel.

[0133] In another embodiment, the long-acting growth hormone preparation includes crystalline growth hormone.

[0134] In another embodiment, the long-acting growth hormone comprises a growth hormone moiety fused to a natural or non-natural amino acid sequence. Preferred amino acid sequences are selected from the group consisting of the following: carboxyl-terminal peptides of chorionic gonadotropins as described in US2012 / 0035101 (incorporated herein by reference); albumin; XTEN sequences as described in WO2011123813A2 (incorporated herein by reference); proline / alanine random coil sequences as described in WO2011 / 144756A1 (incorporated herein by reference); proline / alanine / serine random coil sequences as described in WO2008 / 155134 (incorporated herein by reference); and Fc fusion proteins. Such fusions may be either stable or reversible.

[0135] In another embodiment, the long-acting growth hormone comprises a chemically modified growth hormone or analog thereof, comprising PEGylated hGH and hGH modified with fatty acid derivatives. Preferred fatty acid derivatives are those disclosed in WO2005 / 027978A2 and WO2014 / 060512A1 (incorporated herein by reference). Such chemical modifications in the form of a PEG moiety or a fatty acid derivative moiety can be stably or reversibly bound to the hGH moiety. In one embodiment, the chemical modification is a PEG moiety stably bound to the hGH moiety. In one embodiment, the chemical modification is a PEG moiety reversibly bound to the hGH moiety. In one embodiment, the chemical modification is a fatty acid derivative moiety stably bound to the hGH moiety. In one embodiment, the chemical modification is a fatty acid derivative moiety reversibly bound to the hGH moiety.

[0136] In another embodiment, the long-acting growth hormone is an hGH prodrug in which the hGH moiety is reversibly conjugated to a polymer moiety or a fatty acid-derived moiety. In one embodiment, the hGH moiety is released in an unmodified form from such an hGH prodrug.

[0137] Preferably, the long-acting growth hormone is an hGH polymer prodrug as disclosed in WO05099768A2 and WO2009 / 133137A2 (incorporated herein by reference). Therefore, the long-acting growth hormone is preferably an hGH polymer prodrug of formula (Ia) or (Ib).

[0138] [ka] [In the formula, -D is the hGH moiety that is bonded to the rest of the molecule via an amine functional group. n is 0, 1, 2, 3, or 4. -X- is a chemical bond or spacer, =Y1 and =Y5 are independently selected from the group consisting of =O and =S. -Y2- and -Y3- are selected from the group consisting of -O- and -S-. -Y4- is -O-, -NR 5 - and -C(R 6 R 6a Selected from the group consisting of )-, -R 1 This is a carrier, preferably a water-soluble PEG-based portion containing at least 40% PEG. -R 2 , -R 3 , -R 5 , -R 6 , -R 6aThese are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. -R 4 This is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. -W- is C 3~10 Cycloalkyl, 8-30 membered carbopolycyclyl, 3-10 membered heterocyclyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S- and -N(R 7 )- which may be interrupted by one or more groups selected from the group consisting of C 1~20 Selected from the group consisting of alkyl groups, -Nu is -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH,

[0139] [ka] A nucleophile selected from the group consisting of, -Ar- is,

[0140] [ka] (In the formula, The dashed line indicates the binding of the prodrug to the rest of the body. -Z 1- are -O-, -S- and -N(R 7 Selected from the group consisting of )-, -Z 2 - is -N(R 7 )-is) Selected from the group consisting of, -R 7 , -R 7a , -R 7b is -H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 [Selected independently from the group consisting of alkinyls] And, The prodrugs in formulas (Ia) and (Ib) are sometimes further substituted. It is an hGH polymer prodrug.

[0141] In one embodiment, the long-acting hGH is given by formula (Ia). In another embodiment, the long-acting hGH is given by formula (Ib).

[0142] In a preferred embodiment, equations (Ia) and (Ib) = Y 1 The answer is = O.

[0143] In a preferred embodiment, -Y of formulas (Ia) and (Ib) 2 - is -O-.

[0144] In a preferred embodiment, -Y of formulas (Ia) and (Ib) 3 - is -O-.

[0145] In a preferred embodiment, -Y of formulas (Ia) and (Ib) 4 - is, -NR 5 - is

[0146] In a preferred embodiment, equations (Ia) and (Ib) = Y 5 The answer is = O.

[0147] In a preferred embodiment, n in formulas (Ia) and (Ib) is 0 or 1. Most preferably, n in formulas (Ia) and (Ib) is 0.

[0148] Preferably, the R of formulas (Ia) and (Ib) 1 It has a molecular weight in the range of 10 to 250 kDa, more preferably 15 to 150 kDa.

[0149] In one particularly preferred embodiment, R in formulas (Ia) and (Ib) 1 It has a molecular weight in the range of 30 to 50 kDa, more preferably 35 to 45 kDa, and even more preferably 38 to 42 kDa, and most preferably a molecular weight of about 40 kDa.

[0150] In another equally preferred embodiment, R in formulas (Ia) and (Ib) 1 It has a molecular weight in the range of 60 to 100 kDa, more preferably 70 to 90 kDa, and even more preferably 75 to 85 kDa, and most preferably about 80 kDa.

[0151] Preferably, the R of formulas (Ia) and (Ib) 1 It is branched and contains at least three polymer parts.

[0152] More preferably, R of formulas (Ia) and (Ib) 1 It comprises at least one branch point, preferably at least two branch points, and preferably at least three polymer chains based on PEG, where each branch point is -N<, -CR 8 Preferably selected from the group consisting of < and >C<, R 8 is -H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Selected from the group consisting of alkynnyl, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is one or more identical or different R 9 It is sometimes replaced by C 1~6Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-,-S(O)2N(R 10 )-,-S(O)N(R 10 )-, -S(O)2-, -S(O)-, -N(R 10 )S(O)2N(R 10a )-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )-; may be interrupted by R 9 , R 10 and R 10a is -H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Selected from Alkinyl.

[0153] In a preferred embodiment, R of formulas (Ia) and (Ib) 1 This is the first branching point BP 1 This includes at least two parts C from this branching point 1 and C 2 It is extended, C 1 and C 2 At least one of them is at least the second branch point BP 2 It includes at least two parts P from this branching point 1 and P 2 It extends. More preferably, R 1 This is the first branching point BP 1 This includes two parts C from this branching point. 1 and C 2 It extends, and this part C 1 This is a branching point BP 2 This includes, and from this branching point, at least two parts P 1 and P 2 It extends, part C 2 This is the third branching point BP 3 This includes at least two parts P from this branching point3 and P 4 It will be extended.

[0154] In another preferred embodiment, R 1 This is the first branching point BP 1 , second branching point BP 2 and the third branching point BP 3 Part C including 1 including at least one part P 1 is BP 1 Extending from, at least one part P 2 is BP 2 Extending from, at least one part P 3 is BP 3 It extends from. More preferably, R 1 This is the first branching point BP 1 , second branching point BP 2 , the third branching point BP 3 and the fourth branching point BP 4 Part C including 1 including at least one part P 1 is BP 1 Extending from, at least one part P 2 is BP 2 Extending from, at least one part P 3 is BP 3 Extending from, at least one part P 4 is BP 4 It extends from there.

[0155] Preferably, BP 1 WHITE BP 2 WHITE BP 3 and BP 4 -CR 8 <, >C< and -N< are selected independently of each other, R 8 is -H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Selected from Alkinyl, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is one or more identical or different R 9 It is sometimes replaced by C 1~6Alkyl, C 2~6 Alkenyl and C 2~6 Alkinyl is -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-,-S(O)2N(R 10 )-,-S(O)N(R 10 )-, -S(O)2-, -S(O)-, -N(R 10 )S(O)2N(R 10a )-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )-; may be interrupted by R 9 , R 10 and R 10a is -H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Selected from Alkinyl.

[0156] Preferably, C 1 and C 2 C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Selected independently from each other, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R 11 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-,-N(R12 )C(O)N(R 12a )-, and -OC(O)N(R 12 It is optionally interrupted by one or more elements selected from the group consisting of )-; -T- is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each -T- independently has one or more identical or different R 11 It is sometimes replaced by, R 11 These are halogen, -CN, oxo (=O), and -COOR, respectively. 12 , -OR 12 , -C(O)R 12 ,-C(O)N(R 12 R 12a ), -S(O)2N(R 12 R 12a ), -S(O)N(R 12 R 12a ), -S(O)2R 12 ,-S(O)R 12 , -N(R 12 )S(O)2N(R 12a R 12b ), -SR 12 , -N(R 12 R 12a ), -NO2, -OC(O)R 12 , -N(R 12 )C(O)R 12a , -N(R 12 )S(O)2R 12a , -N(R 12 )S(O)R 12a , -N(R 12 )C(O)OR 12a , -N(R 12 )C(O)N(R 12a R 12b ), -OC(O)N(R 12 R 12a ), and C 1~6 Independently selected from the group consisting of alkyl, C 1~6Alkyl is optionally substituted with one or more identical or different halogens. R 12 , R 12a and R 12b These are -H and C, respectively. 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Selected independently from the group consisting of alkynnyls, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are optionally substituted with one or more identical or different halogens.

[0157] Preferably, P 1 , P 2 , P 3 , P 4 These are, independently of each other, polymer moieties, more preferably PEG-based chains, comprising at least 40% PEG, more preferably at least 50% PEG, more preferably at least 60% PEG, more preferably at least 70% PEG, more preferably at least 80% PEG, more preferably at least 90% PEG, and most preferably at least 95% PEG.

[0158] In one preferred embodiment, P 1 , P 2 , P 3 and P 4 These molecules independently have molecular weights in the range of 5 kDa to 20 kDa, more preferably in the range of 7 to 15 kDa, and even more preferably in the range of 8 to 12 kDa, with most preferably having a molecular weight of about 10 kDa.

[0159] Similarly, in a preferred embodiment, P 1 , P 2 , P 3 and P 4 These molecules independently have molecular weights in the range of 10 to 30 kDa, more preferably 15 to 25 kDa, and even more preferably 17 to 23 kDa, with most preferably a molecular weight of about 20 kDa.

[0160] In a preferred embodiment, the -R of formulas (Ia) and (Ib) 1 This is part of equation (II)

[0161] [ka] (In the formula, -BP 1 <, -BP 2 <, -BP 3 < is -N< and -C(R 8 Selected independently from the group consisting of )<, R 8 H, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Selected from the group consisting of alkynnyls, -P 1 , -P 2 , -P 3 , -P 4 These are PEG-based chains that independently contain at least 40% PEG and have a molecular weight in the range of 5 to 30 kDa. -C 1 -, -C 2 - is C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Selected independently from the group consisting of alkynnyls, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R 9 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-,-S(O)2N(R 10 )-,-S(O)N(R 10 )-, -S(O)2-, -S(O)-, -N(R 10 )S(O)2N(R 10a )-, -S-, -N(R 10)-, -OC(OR 10 )(R 10a )-, -N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )-; optionally interrupted by one or more groups selected from the group consisting of, T is each independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic and 8- to 30-membered heteropolycyclic, and T is each optionally independently substituted by one or more identical or different R 9 ; R 9 is each independently halogen, -CN, oxo (=O), -COOR 11 , -OR 11 , -C(O)R 11 , -C(O)N(R 11 R 11a ), -S(O)2N(R 11 R 11a ), -S(O)N(R 11 R 11a ), -S(O)2R 11 , -S(O)R 11 , -N(R 11 )S(O)2N(R 11a R 11b ), -SR 11 , -N(R 11 R 11a ), -NO2, -OC(O)R 11 , -N(R 11 )C(O)R 11a , -N(R 11 )S(O)2R 11a , -N(R 11 )S(O)R 11a , -N(R 11 )C(O)OR 11a , -N(R 11 )C(O)N(R 11a R 11b ), -OC(O)N(R 11 R 11a ), and C 1~6Independently selected from the group consisting of alkyl, C 1~6 Alkyl is optionally substituted with one or more identical or different halogens. R 10 , R 10a , R 11 , R 11a and R 11b These are -H and C, respectively. 1~6 Independently selected from the group consisting of alkyls, C 1~6 Alkyl is sometimes substituted with one or more identical or different halogens. Includes.

[0162] In a preferred embodiment, BP of formula (II) 1 -N < .

[0163] In a preferred embodiment, BP of formula (II) 2 and BP 2 Both are -CH<.

[0164] First branching point BP 1 It is advantageous if the bonding sites of X are separated by fewer than a certain number of atoms.

[0165] Preferably, the important distances in the prodrugs of formulas (Ia) and (Ib) are less than 60 atoms, more preferably less than 50 atoms, even more preferably less than 40 atoms, even more preferably less than 30 atoms, even more preferably less than 20 atoms, and most preferably less than 10 atoms.

[0166] The term "important distance" refers to the case where the prodrug is given by formula (Ia), R 1 The first branch point BP included 1 This refers to the shortest distance measured as the number of atoms between and the atom marked with an asterisk in formula (a), or, if the prodrug is formula (Ib), R 1 The first branch point BP included 1 This refers to the number of atoms between the atom marked with an asterisk in equation (b):

[0167] [ka] (In the formulas, the dashed lines indicate the binding of the prodrug of formula (Ia) to the remainder in the case of (a), and the binding of the prodrug of formula (Ib) to the remainder in the case of (b).)

[0168] In a preferred embodiment, -P of formula (II) 1 , -P 2 , -P 3 , -P 4 These molecules independently have molecular weights in the range of 5 kDa to 20 kDa, more preferably in the range of 7 to 15 kDa, and even more preferably in the range of 8 to 12 kDa, with most preferably having a molecular weight of about 10 kDa.

[0169] Similarly, in a preferred embodiment, -P of formula (II) 1 , -P 2 , -P 3 , -P 4 These molecules independently have molecular weights in the range of 10 to 30 kDa, more preferably 15 to 25 kDa, and even more preferably 17 to 23 kDa, with most preferably a molecular weight of about 20 kDa.

[0170] In a preferred embodiment, C of formula (II) 1 and C 2 is -O-, -C(O)N(R 10 )- and C interrupted by one or more groups selected from the group consisting of 3- to 10-membered heterocyclines 1~50 The alkyl group, a 3- to 10-membered heterocyclyl, is substituted with at least one oxo (=O) atom.

[0171] Most preferably, C of formula (II) 1 and C 2 is equation (IIa)

[0172] [ka] (In the formula, The dashed lines marked with an asterisk are BP 1 This shows a connection to, The dashed lines without markings are BP 2 or BP 3 This shows a connection to, q1 is 1, 2, 3, 4, 5, 6, 7, or 8, preferably q1 is 4, 5, 6, 7, or 8, more preferably q1 is 5, 6, or 7, and most preferably q1 is 6. q2 is 1, 2, 3, 4, or 5, preferably q2 is 1, 2, or 3, and most preferably q2 is 2. q3 is 1, 2, 3, 4, 5, 6, 7, or 8, preferably q3 is 2, 3, 4, or 5, more preferably q3 is 2, 3, or 4, and most preferably q3 is 3. (q4 is 1, 2, or 3, and most preferably q4 is 1) That is the case.

[0173] In a preferred embodiment, P of formula (II) 1 , P 2 , P 3 and P 4 These are independent of each other, and equation (IIb)

[0174] [ka] (In the formula, The dashed line is R 1 The remainder, that is, each, BP 2 or BP 3 This shows a connection to, m is either 0 or 1. p is an integer in the range of 57 to 1420, more preferably 85 to 850. (q is selected from the group consisting of 1, 2, 3, 4, 5, and 6) That is the case.

[0175] In a preferred embodiment, p in formula (IIb) is in the range of 170 to 284, more preferably 198 to 255, and most preferably 215 to 238.

[0176] Similarly, in a preferred embodiment, p in formula (IIb) is in the range of 340 to 568, more preferably 398 to 510, and most preferably 426 to 482.

[0177] Comfortably, -R 1 This is part of equation (IIc):

[0178] [ka] (In the formula, p1, p2, p3, and p4 are independent integers in the range of 57 to 1420, more preferably 85 to 850. Includes.

[0179] In a preferred embodiment, p1, p2, p3, and p4 in formula (IIc) are integers independently selected from 170 to 284, more preferably 198 to 255, and most preferably 215 to 238.

[0180] Similarly, in a preferred embodiment, p1, p2, p3, and p4 in formula (IIc) are integers independently selected from 340 to 568, more preferably 398 to 510, and most preferably 426 to 482.

[0181] In a preferred embodiment, -R of formula (Ib) 2 The is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. More preferably, the -R of formula (Ib) 2 The is selected from the group consisting of -H, methyl, ethyl, n-propyl and isopropyl. More preferably, the -R of formula (Ib) 2 is selected from -H, methyl and ethyl. Most preferably, -R of formula (Ib) 2 It is -H.

[0182] In a preferred embodiment, the -R of formulas (Ia) and (Ib) 3is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 3 is selected from the group consisting of -H, methyl, ethyl, n-propyl and isopropyl. Even more preferably, -R in formulas (Ia) and (Ib) 3 is selected from -H, methyl and ethyl. Most preferably, -R in formulas (Ia) and (Ib) 3 is -H.

[0183] In a preferred embodiment, -R in formulas (Ia) and (Ib) 4 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl respectively. More preferably, -R in formulas (Ia) and (Ib) 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl. Even more preferably, -R in formulas (Ia) and (Ib) 4 is selected from methyl and ethyl.

[0184] In a preferred embodiment, -R in formulas (Ia) and (Ib) 5 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 5 is selected from the group consisting of -H, methyl, ethyl, n-propyl and isopropyl. Even more preferably, -R in formulas (Ia) and (Ib) 5 is selected from methyl and ethyl. Most preferably, -R in formulas (Ia) and (Ib) 5 is methyl.

[0185] In a preferred embodiment, -R in formulas (Ia) and (Ib) 6 and -R 6aThe -R of formulas (Ia) and (Ib) is independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 6 and -R 6a is independently selected from the group consisting of -H, methyl, ethyl, n-propyl and isopropyl. More preferably, -R of formulas (Ia) and (Ib). 6 and -R 6a is independently selected from -H, methyl, and ethyl. Most preferably, -R of formulas (Ia) and (Ib). 6 and -R 6a Both are -H.

[0186] In a preferred embodiment, X in formulas (Ia) and (Ib) is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R z1 )-,-S(O)2N(R z1 )-,-S(O)N(R z1 )-, -S(O)2-, -S(O)-, -N(R z1 )S(O)2N(R z1a )-, -S-, -N(R z1 )-, -OC(OR z1 )(R z1a )-,-N(R z1 )C(O)N(R z1a )-,-OC(O)N(R z1 )-, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Preferably selected from the group consisting of alkynyl, -T-,C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-,-S(O)2N(R z3 )-,-S(O)N(R z3)-, -S(O)2-, -S(O)-, -N(R z3 )S(O)2N(R z3a )-, -S-, -N(R z3 )-, -OC(OR z3 )(R z3a )-,-N(R z3 )C(O)N(R z3a )-, and -OC(O)N(R z3 It is optionally interrupted by one or more elements selected from the group consisting of )-; R z1 and R z1a -H, -T, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Selected independently from the group consisting of alkynnyls, -T, C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~50 Alkyl, C 2~50 Alkenyl and C 2~50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z4 )-,-S(O)2N(R z4 )-,-S(O)N(R z4 )-, -S(O)2-, -S(O)-, -N(R z4 )S(O)2N(R z4a )-, -S-, -N(R z4 )-, -OC(OR z4 )(R z4a )-,-N(R z4 )C(O)N(R z4a )-, and -OC(O)N(R z4 It is optionally interrupted by one or more elements selected from the group consisting of )-; T represents phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C respectively. 3~10Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, T is independently selected from the group consisting of one or more identical or different R z2 It is sometimes replaced by, R z2 These are halogen, -CN, oxo (=O), and -COOR, respectively. z5 , -OR z5 , -C(O)R z5 ,-C(O)N(R z5 R z5a ), -S(O)2N(R z5 R z5a ), -S(O)N(R z5 R z5a ), -S(O)2R z5 ,-S(O)R z5 , -N(R z5 )S(O)2N(R z5a R z5b ), -SR z5 , -N(R z5 R z5a ), -NO2, -OC(O)R z5 , -N(R z5 )C(O)R z5a , -N(R z5 )S(O)2R z5a , -N(R z5 )S(O)R z5a , -N(R z5 )C(O)OR z5a , -N(R z5 )C(O)N(R z5a R z5b ), -OC(O)N(R z5 R z5a ), and C 1~6 Independently selected from the group consisting of alkyl, C 1~6 Alkyl is optionally substituted with one or more identical or different halogens. R z3 , R z3a , R z4 , R z4a , R z5 , R z5a and R z5b These are -H and C, respectively.1~6 Independently selected from the group consisting of alkyls, C 1~6 Alkyl atoms are optionally substituted with one or more identical or different halogens.

[0187] More preferably, X in formulas (Ia) and (Ib) is C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 Selected from the group consisting of alkynnyl, C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 Alkinyl is one or more identical or different R z2 It is sometimes replaced by C 1~10 Alkyl, C 2~10 Alkenyl and C 2~10 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-,-S(O)2N(R z3 )-,-S(O)N(R z3 )-, -S(O)2-, -S(O)-, -N(R z3 )S(O)2N(R z3a )-, -S-, -N(R z3 )-, -OC(OR z3 )(R z3a )-,-N(R z3 )C(O)N(R z3a )-, and -OC(O)N(R z3 It is optionally interrupted by one or more elements selected from the group consisting of )-; T represents phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C respectively. 3~10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, T is independently selected from the group consisting of one or more identical or different R z2 It is sometimes replaced by, R z2 These are C 1~6 Selected independently of alkyl, C 1~6Alkyl is optionally substituted with one or more identical or different halogens. R z3 , R z3a These are -H and C, respectively. 1~6 Independently selected from the group consisting of alkyls, C 1~6 Alkyl atoms are optionally substituted with one or more identical or different halogens.

[0188] More preferably, X in formulas (Ia) and (Ib) is -C(O)O-, -O-, -C(O)-, -C(O)N(R z3 )-, -S-, -N(R z3 )-, -OC(OR z3 )(R z3a )- and -OC(O)N(R z3 C is optionally interrupted by one or more groups selected from the group consisting of )- 1~10 It is alkyl, R z3 and R z3a -H and C 1~6 It is selected independently of alkyl.

[0189] Most preferably, X in formulas (Ia) and (Ib) is formula (III)

[0190] [ka] (In the formula, The dashed line marked with an asterisk is R 1 This shows a connection to, Unmarked dashed lines indicate the binding of the prodrug to the rest of the body. (q5 is 1, 2, 3, 4, 5, 6, 7, or 8, preferably q5 is 1, 2, 3, 4, or 5, more preferably q5 is 2, 3, or 4, and most preferably q5 is 3) That is the case.

[0191] Preferably, the Ar in formulas (Ia) and (Ib) is phenyl. Most preferably, the Ar in formulas (Ia) and (Ib) is

[0192] [ka] (In the formulas, the dashed line indicates the binding of the prodrug of formula (Ia) or (Ib) to the remainder.) That is the case.

[0193] Preferably, W in formulas (Ia) and (Ib) is C 3~10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S- and -N(R 7 )- which may be interrupted by C 1~20 It is alkyl. More preferably, W in formulas (Ia) and (Ib) is C 3~10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S- and -N(R 7 )- which may be interrupted by C 1~10 It is alkyl. More preferably, W in formulas (Ia) and (Ib) is C 3~10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S- and -N(R 7 )- which may be interrupted by C 1-6 It is alkyl. Most preferably, W in formulas (Ia) and (Ib) is

[0194] [ka] (In the formula, (The dashed lines indicate the bonding of the molecule to the rest of the molecule.) That is the case.

[0195] Preferably, -Nu in formulas (Ia) and (Ib) is -N(R 7 R 7a )

[0196] Preferably, the -R of formulas (Ia) and (Ib) 7 and -R 7aThe group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl is independently selected from each other. More preferably, the -R of formulas (Ia) and (Ib) 7 and -R 7a The -R of formulas (Ia) and (Ib) is independently selected from -H, methyl, ethyl, n-propyl, and isopropyl. More preferably, the -R of formulas (Ia) and (Ib) is selected independently from each other. 7 and -R 7a The compound is independently selected from methyl or ethyl. Most preferably, the -R of formulas (Ia) and (Ib). 7 and -R 7a Both are methyl.

[0197] Most preferably, the long-acting growth hormone is an hGH polymer prodrug of formula (IV).

[0198] [ka] (In the formula, D is the hGH moiety that is bonded to the rest of the molecule via an amine functional group. p1, p2, p3, and p4 are independent integers in the range of 57 to 1420, more preferably 85 to 850. That is the case.

[0199] In a preferred embodiment, p1, p2, p3, and p4 in formula (IV) are integers independently selected from 170 to 284, more preferably 198 to 255, and most preferably 215 to 238.

[0200] Similarly, in a preferred embodiment, p1, p2, p3, and p4 in formula (IV) are integers independently selected from 340 to 568, more preferably from 398 to 510, and most preferably from 426 to 482.

[0201] Preferably, the long-acting growth hormone preparation comprises at least one long-acting growth hormone selected from the group consisting of ACP-001, ACP-011, VRS-317, MOD-4023, somatorogon, hGH-CTP, albutropin, ARX201, ALTU-238, PHA-794428, hGH-OctoDex, NNC126-0083, somapsitan, somabalatan, Nutropin Depot, LB03002, somatropin BioPartners, LAPS-hGH, NNC0195-0092, Hytropin, GX-H9, Jintrolong, and TV-1106.

[0202] In one embodiment, the long-acting growth hormone is ACP-001. ACP-001 has the structure of formula (IV), where p1, p2, p3, and p4 are in the range of 398 to 510, meaning that the molecular weight of the four PEG moieties is approximately 80 kDa.

[0203] In one embodiment, the long-acting growth hormone is ACP-011. ACP-011 has the structure of formula (IV), where p1, p2, p3, and p4 are in the range of 198 to 255, meaning that the molecular weight of the four PEG moieties is approximately 40 kDa.

[0204] In one embodiment, the long-acting growth hormone is somapsitan. Somapsitan has the following structure:

[0205] [ka] (In the formula, the dashed line indicates, (This shows the bond of cysteine ​​to sulfur at position 101 of sequence number 2, TIFF2026113655000020.tif30166.) It has.

[0206] Sequence ID 2 corresponds to Sequence ID 1, in which the leucine at position 101 is replaced by cysteine.

[0207] In one embodiment, the pharmaceutical composition containing a long-acting growth hormone is a liquid formulation.

[0208] In another embodiment, the pharmaceutical composition containing the long-acting growth hormone is a dry formulation.

[0209] In a preferred embodiment, the pharmaceutical composition containing the long-acting growth hormone is stable at refrigerated temperatures, i.e., 2-8°C, for at least 3 months.

[0210] In another preferred embodiment, the pharmaceutical composition containing the long-acting growth hormone is stable at room temperature, i.e., 18-30°C, for at least 3 months.

[0211] In another preferred embodiment, long-acting growth hormone is administered in combination with a C-type natriuretic peptide agonist.

[0212] In another preferred embodiment, a long-acting growth hormone is administered in combination with soluble FGFR3.

[0213] Such liquid or dry pharmaceutical compositions containing long-acting growth hormone contain one or more excipients. Excipients used in parenteral formulations can be classified, for example, as buffers, isotonic modifiers, preservatives, stabilizers, anti-adsorbents, antioxidants, viscosifiers / viscosity enhancers, or other adjuvants. However, in some cases, one excipient may have two or three functions. Pharmaceutical compositions containing long-acting growth hormone preferably contain one or more excipients selected from the group consisting of: (i) Buffering agent: A physiologically acceptable buffer that maintains the pH within the desired range, such as sodium phosphate, sodium bicarbonate, sodium succinate, sodium histidine, sodium citrate and sodium acetate, sodium sulfate, sodium nitrate, sodium chloride and sodium pyruvate. Antacids, such as Mg(OH)2 or ZnCO3, may also be used. (ii) Isotonic modifiers: To minimize pain that may result from cell damage due to osmotic pressure differences in the injectable depot preparation. Examples include glycerin and sodium chloride. The effective concentration can be determined by osmotic method using an estimated osmolality of 285-315 mOsmol / kg in serum. (iii) Preservatives and / or antimicrobial agents: Parenteral formulations for multiple doses must be supplemented with preservatives at concentrations sufficient to minimize the risk of patient infection at injection, and corresponding regulatory requirements have been established. Typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercury nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride. (iv) Stabilizers: Stabilization is achieved by enhancing the protein stabilizing power, by destabilizing the denatured state, or by direct binding of excipients to the protein. Stabilizers can be amino acids, such as alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; sugars, such as glucose, sucrose, trehalose; polyols, such as glycerol, mannitol, sorbitol; salts, such as potassium phosphate, sodium sulfate; chelating agents, such as EDTA, hexaphosphate; ligands, such as divalent metal ions (zinc, calcium, etc.); other salts; or organic molecules, such as phenol derivatives. Furthermore, oligomers or polymers, such as cyclodextrin, dextran, dendrimers, PEG or PVP, or protamine or HSA can be used.

[0214] (v) Antiadsorbents: Primarily ionic or nonionic surfactants or other proteins or soluble polymers are used to competitively coat or adsorb onto the inner surface of the formulation container. Examples include poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin. The selected concentration and type of excipient depends on the action to be avoided, but typically a single layer of surfactant is formed at the interface just above the CMC value. (vi) Oxidative protective agents: Antioxidants such as ascorbic acid, ectoin, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, and vitamin E. Chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid may also be used. (vii) Thickening agents or viscosity enhancers: These are used to delay the sedimentation of particles in vials and syringes, to facilitate the mixing and resuspension of particles, and to make the suspension easier to inject (i.e., with less force on the syringe plunger). Suitable thickening agents or viscosity enhancers include, for example, carbomer thickening agents such as Carbopol 940 and Carbopol Ultrez 10, cellulose derivatives such as hydroxypropyl methylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (DEAE or DEAE-C), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthan gum, carrageenan such as Satia gum UTC 30. Aliphatic poly(hydroxy acids), e.g., poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and copolymers thereof (PLGA), terpolymers of D,L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks for forming three blocks of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) (e.g., Pluronic®), polyether ester copolymers, e.g., polyethylene glycol terephthalate / polybutylene terephthalate copolymer, sucrose acetate isobutyrate (SAIB), dextran or its derivatives. The material is an ABA triblock or AB block copolymer, composed of a body, a combination of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and its derivatives, polyalkylimide, poly(acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAG), such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan, a hydrophobic A block, such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA), and a hydrophilic B block, such as polyethylene glycol (PEG) or polyvinylpyrrolidone. Such block copolymers and the aforementioned poloxanes. Summer may exhibit reverse thermal gelation behavior (a fluid state at room temperature to facilitate administration, and a gel state at temperatures higher than the sol-gel transition temperature at body temperature after injection). (viii) Spreaders or diffusing agents: Components of the extracellular matrix in the interstitial space, such as hyaluronic acid, a polysaccharide found in the intercellular space of connective tissue, which modifies the permeability of connective tissue by hydrolysis. Spreaders, such as hyaluronidase, which is not limited to the following, temporarily reduce the viscosity of the extracellular matrix and promote the diffusion of the injected drug. (ix) Other auxiliary agents: e.g., wetting agents, viscosity modifiers, antibiotics, hyaluronidase. Acids and bases, e.g., hydrochloric acid and sodium hydroxide, are necessary auxiliary agents for pH adjustment during manufacturing.

[0215] Another aspect of the present invention is a method for treating a patient suffering from a growth disorder, comprising the step of administering to the patient an effective amount of the long-acting growth hormone preparation of the present invention. The administration of the long-acting growth hormone yields superior efficacy compared to an equimolar administration of somatropin on a daily basis.

[0216] In one embodiment, the superior efficacy is measured as an annualized rate of height growth.

[0217] Another aspect of the present invention is a method for treating growth hormone deficiency, comprising the step of administering a long-acting growth hormone preparation to a patient having growth hormone deficiency, wherein the administration of the long-acting growth hormone results in a reduction in unresponsive individuals compared to the administration of an equimolar dose of somatropin daily.

[0218] Preferably, the long-acting growth hormone preparation is administered to the patient with at least two days between doses. More preferably, the period between doses is at least three days, even more preferably at least four days, even more preferably at least five days, even more preferably at least six days, and most preferably, the period between doses is seven days. In another embodiment, the period between doses is 14 days or one month.

[0219] Preferably, growth hormone deficiency is treated for a period of at least 6 months, for example, at least 8 months, for example, at least 10 months, for example, at least 12 months, for example, at least 14 months, for example, at least 16 months, for example, at least 20 months, for example, at least 24 months, for example, at least 30 months, or for example, at least 36 months.

[0220] Another aspect of the present invention is a method for administering a long-acting growth hormone preparation to a patient with growth hormone deficiency, wherein the administration of the long-acting growth hormone yields superior efficacy compared to the administration of an equimolar dose of somatropin daily.

[0221] As used herein, the term “growth hormone deficiency” refers to any disease for which the administration of growth hormone is effective. Preferably, growth hormone deficiency is selected from the group consisting of growth hormone deficiency (GHD), idiopathic short stature (ISS), short stature homeobox (SHOX) gene mutation, Turner syndrome (TS), Noonan syndrome (NS), Prader-Willi syndrome (PWS), intrauterine growth retardation (SGA), chronic renal failure (CRI), growth hormone deficiency (GHD) in adults, wasting due to HIV or AIDS or other malignant diseases, short bowel syndrome (SBS), sarcopenia, and frailty.

[0222] In another embodiment, growth hormone deficiency is GHD in adults. In another embodiment, growth hormone deficiency is ISS. In another embodiment, growth hormone deficiency is a SHOX gene mutation. In another embodiment, growth hormone deficiency is TS. In another embodiment, growth hormone deficiency is NS. In another embodiment, growth hormone deficiency is PWS. In another embodiment, growth hormone deficiency is SGA. In another embodiment, growth hormone deficiency is CRI. In another embodiment, growth hormone deficiency is wasting due to HIV or AIDS or other malignant diseases. In another embodiment, growth hormone deficiency is SBS. In another embodiment, growth hormone deficiency is sarcopenia. In another embodiment, growth hormone deficiency is frailty. In a preferred embodiment, growth hormone deficiency is GHD in children.

[0223] [Examples] method Cation exchange chromatography The conjugate was purified by cation exchange chromatography using an AKTA Pure system (GE Healthcare) equipped with a Macrocap SP column with a column volume of 279 mL. Each reaction mixture was applied to a column pre-equilibriumated in 20 mM sodium acetate, 10 mM L-methionine buffer, pH 4.0 (Buffer A). After loading, the column was washed with Buffer A equivalent to three column volumes to remove any unreacted PEG reagent. The mono-conjugate was eluted using a gradient of 0-30% Buffer B (20 mM sodium acetate, 1 M sodium chloride, pH 4.5) equivalent to a total of 15 column volumes. Unreacted growth hormone was eluted using a gradient of 30-80% Buffer B equivalent to three column volumes. The column was then cleaned with 100% Buffer B equivalent to three column volumes. The flow rate was 20 mL / min during loading and 25 mL / min during elution. Elution was monitored by detection at 280 nm.

[0224] Measurement of height and height growth rate Height measurements were taken using a graduated wall-mounted studio meter (e.g., Harpenden or similar). The results were derived as the arithmetic mean of three separate measurements taken during each visit. The time of measurement, the name of the auxologist, and the results were recorded. Intensive calculations of height growth rate were performed.

[0225] [Example 1] Synthesis of transient 4×10kDa mPEG-linker-hGH monoconjugate 1

[0226] [ka] 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 was synthesized following a procedure similar to that described in WO2009 / 133137A2. In detail, this manufacturing method was carried out as follows.

[0227] hGH was buffered with 100 mM sodium borate pH 9 to adjust the hGH concentration to 10 mg / mL. A 4 × 10 kDa branched 40 kDa mPEG-pentafluorophenyl carbonate derivative with four arms in excess of the amount of hGH was dissolved in water to form a 6% (w / w) reagent solution. This reagent solution was added to the hGH solution in a 1:1 ratio (by weight) and mixed. The reaction mixture was incubated at 12–16°C for 105 minutes with stirring, and then quenched by adding 4 volumes of a solution containing 27 mM acetic acid and 12.5 mM L-methionine to 1 volume of the reaction mixture, lowering the pH of the solution to 4–4.5. After sterile filtration, the reaction mixture was incubated at room temperature for 16 ± 4 hours. 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 was purified by cation exchange chromatography.

[0228] Buffer exchange and adjustment of 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 to the desired concentration were achieved using a tangential flow filtration system. The eluent from cation exchange chromatography was then ultrafiltered and dialyzed to a formulation buffer (10 mM succinic acid, 85 g / L trehalose dihydrate, pH 5.0 with 1 M Tris solution). Using the same system, the trehalose concentration was reduced to 65 g / L, adjusting the concentration of this storage solution to 105 ± 3 mg / mL of 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 (equivalent to 35 ± 1 mg of hGH / mL). The formulations shown in Table 2 were prepared by diluting this storage solution of compound 1 with a high-strength formulation buffer (10 mM succinic acid, 89 g / L trehalose dihydrate, pH 5.0 adjusted with 1 M Tris base).

[0229] [Table 1]

[0230] [Example 2] Preparation of a formulation containing 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 for clinical research

[0231] For use as an investigational drug in clinical research, 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 was converted into a lyophilized drug product in glass vials and supplied as a lyophilized powder for reconstitution by sWFI in single-use glass vials, formulated at concentrations suitable for delivering clinically relevant dose volumes (≤0.60 mL) for pediatric patients. This was supplied in two vial configurations: 12.1 mg hGH / vial and 24.2 mg hGH / vial.

[0232] [Table 2]

[0233] After reconstitution with water for injection (WFI), 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 was provided as a single-use sterile solution for subcutaneous (sc) injection.

[0234] [Example 3] Phase 3 Pediatric Study The formulation of Example 3, containing 4 × 10 kDa mPEG-linker-hGH monoconjugate 1, was studied in a Phase 3 pediatric growth hormone deficiency study. Pediatric patients meeting internationally recognized criteria for GHD, including short stature as measured by height and height growth rate, two hGH stimulation tests, bone age assessment, and IGF-I levels below -1 standard deviation score or SDS, were enrolled across North America, Europe, and Oceania. This Phase 3 study was a multicenter, open-label trial that enrolled approximately 161 untreated children with GHD, randomized in a 2:1 ratio to receive either 4 × 10 kDa mPEG-linker-hGH monoconjugate 1 once weekly (0.24 mg / kg / week subcutaneously) or Genotropin® daily (34 μg / kg / day or 0.24 mg / kg / week subcutaneously) for 52 weeks. The primary endpoint was annualized HV at week 52. Secondary endpoints included safety and tolerability; annualized HV over 52 weeks; changes in height standard deviation score (SDS) over 52 weeks; serum IGF-1 and IGFBP-3 levels and corresponding changes in SDS over 52 weeks; and the incidence of anti-human growth hormone antibodies, including neutralizing antibodies. Furthermore, both arms were analyzed for unresponsive individuals.

[0235] In conclusion, a randomized, open-label, active-controlled trial demonstrated that 4×10kDa mPEG-linker-hGH monoconjugate 1 (n=105) met its primary objective of non-inferiority and was superior to daily genotropin (n=56) in the primary endpoint of annualized height growth rate (AHV) at week 52. In a primary analysis of the treatment intention population using ANCOVA, 4×10kDa mPEG-linker-hGH monoconjugate 1 showed an AHV of 11.2 cm / year compared to 10.3 cm / year with daily hGH. The difference between treatments was 0.86 cm / year with a 95 percent confidence interval of +0.22 to +1.50 cm / year, demonstrating superiority (p=0.0088).

[0236] AHV was greater in the 4×10kDa mPEG-linker-hGH monoconjugate 1 group than in the daily hGH group at each visit, and the difference between treatments reached statistical significance from week 26 and continued throughout the trial. The incidence of low-response individuals (AHV < 8.0 cm / year) was 4 percent and 11 percent in the 4×10kDa mPEG-linker-hGH monoconjugate 1 and daily hGH groups, respectively.

[0237] 4×10kDa mPEG-linker-hGH monoconjugate 1 was safe and well-tolerated, with adverse events typical of daily hGH treatment and comparable across arms. Furthermore, observed peak and trough insulin-like growth factor 1 (IGF-1) SDS levels were approximately +1.3 and -0.5 over 52 weeks for 4×10kDa mPEG-linker-hGH monoconjugate 1, compared to an approximate mean IGF-1 SDS of 0.0 at week 52 for daily hGH, respectively. Additionally, observed deviations of IGF-1 SDS > 2.0 were rare (<10 percent of subjects), and IGF-1 SDS > 3.0 was uncommon (<3 percent of subjects). Two subjects in each treatment arm experienced injection site reactions considered to be adverse events.

[0238] [Example 4] Phase 2 Pediatric Study: Somapsitan (NCT02616562, Novo Nordisk; https: / / clinicaltrials.gov / ct2 / show / NCT02616562) Somapsitan has the structure shown elsewhere in this specification.

[0239] Design: The study was a multicenter, randomized, controlled, double-blind, phase 2 (somapsitan dose) study conducted at 29 locations in 11 countries, consisting of a 26-week main phase and a 26-week extension phase. Fifty-nine GH-untreated pre-pubescent children with GHD were randomized, and 58 completed the trial.

[0240] Intervention: Three doses of somapsitan (0.04 mg / kg / week [n=16], 0.08 mg / kg / week [n=15], or 0.16 mg / kg / week [n=14]) and daily GH (0.034 mg / kg / day [n=14]) were administered subcutaneously.

[0241] Primary outcome measure: The primary endpoint was HV at week 26. Secondary efficacy endpoints included HV SDS and IGF-I SDS.

[0242] Results: At week 26, the mean (SD) annualized HV in the somapsitan group was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm / year, respectively, compared to 11.4 (3.3) cm / year in the daily GH group. The estimated difference due to treatment (somapsitan 0.16 mg / kg / week - daily GH) was 1.7 [95% CI - 0.2; 3.6] cm / year. HV was maintained at week 52, and was significantly greater with somapsitan 0.16 mg / kg / week compared with daily GH. The mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) in the somapsitan group, respectively, compared to 7.41 (4.08) in the daily GH group. The model-derived mean (SD) IGF-I SDS for the somapsitan group were -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, while a daily GH of -0.40 (1.50) was observed. Safety and tolerability were consistent with the daily GH profile.

[0243] Abbreviation AHV Annual / annualized height growth rate API Active Pharmaceutical Ingredients cGMP Current Good Manufacturing Practice GH Growth Hormone GHD (Growth Hormone Deficiency) hGH (Human Growth Hormone) mPEG Methoxypoly(ethylene glycol) PEG Poly(ethylene glycol) Ph. Eur. European Pharmacopoeia USP (United States Pharmacopeia) Tris (Hydroxymethyl)-aminomethane

[0244] [Sequence List] SEQUENCE LISTING <110> Ascendis Pharma Endocrinology Division A / S <120> Long-Acting Growth Hormone Dosage Forms With Superior Efficacy to Daily Somatropin <130> PA26-139 <140> JP 2021-552133 <141> 2020-03-03 <150> EP19160459.4 <151> 2019-03-04 <160> 2 <170> PatentIn version 3.5 <210> 1 <211> 191 <212> PRT <213> Homo sapiens <400> 1 Phe Pro Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg 1 5 10 15 Ala His Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu 20 25 30 Glu Ala Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro 35 40 45 Gln Thr Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg 50 55 60 Glu Glu Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu 65 70 75 80 Leu Leu Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val 85 90 95 Phe Ala Asn Ser Leu Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp 100 105 110 Leu Leu Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu 115 120 125 Glu Asp Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser 130 135 140 Lys Phe Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr 145 150 155 160 Gly Leu Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe 165 170 175 Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe 180 185 190 <210> 2 <211> 191 <212> PRT <213> Artificial Sequence <220> <223> L101C mutant of human growth hormone <400> 2 Phe Pro Thr Ile Pro Leu Ser Arg Leu Phe Asp Asn Ala Met Leu Arg 1 5 10 15 Ala His Arg Leu His Gln Leu Ala Phe Asp Thr Tyr Gln Glu Phe Glu 20 25 30 Glu Ala Tyr Ile Pro Lys Glu Gln Lys Tyr Ser Phe Leu Gln Asn Pro 35 40 45 Gln Thr Ser Leu Cys Phe Ser Glu Ser Ile Pro Thr Pro Ser Asn Arg 50 55 60 Glu Glu Thr Gln Gln Lys Ser Asn Leu Glu Leu Leu Arg Ile Ser Leu 65 70 75 80 Leu Leu Ile Gln Ser Trp Leu Glu Pro Val Gln Phe Leu Arg Ser Val 85 90 95 Phe Ala Asn Ser Cys Val Tyr Gly Ala Ser Asp Ser Asn Val Tyr Asp 100 105 110 Leu Leu Lys Asp Leu Glu Glu Gly Ile Gln Thr Leu Met Gly Arg Leu 115 120 125 Glu Asp Gly Ser Pro Arg Thr Gly Gln Ile Phe Lys Gln Thr Tyr Ser 130 135 140 Lys Phe Asp Thr Asn Ser His Asn Asp Asp Ala Leu Leu Lys Asn Tyr 145 150 155 160 Gly Leu Leu Tyr Cys Phe Arg Lys Asp Met Asp Lys Val Glu Thr Phe 165 170 175 Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe 180 185 190

Claims

1. A long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, for use in a method to reduce the percentage of unresponsive individuals in a patient population suffering from growth hormone deficiency.

2. The long-acting growth hormone or pharmaceutical preparation according to claim 1, wherein the percentage of unresponsive individuals is reduced to less than 10%.

3. A long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, for use in the treatment of growth hormone deficiency, wherein the treatment increases plasma IGF-1 levels by a standard deviation score at least 0.2 greater than that of an equivalent daily dose of hGH.

4. The long-acting growth hormone or pharmaceutical formulation according to claim 3, wherein the increase is at least 0.3 SDS.

5. A long-acting growth hormone, or a pharmaceutical formulation containing such a long-acting growth hormone, for use in a method of increasing the percentage of responding individuals in a patient population suffering from growth hormone deficiency.

6. The long-acting growth hormone or pharmaceutical formulation according to claim 5, wherein the percentage of responding individuals is increased to at least 90%.

7. A long-acting growth hormone or a pharmaceutical preparation containing a long-acting growth hormone for use in a method of treatment, wherein the long-acting growth hormone or pharmaceutical preparation is administered at a dose of 0.24 mg / kg / week of growth hormone or an equivalent amount of growth hormone, and the administration of the long-acting growth hormone or the pharmaceutical composition containing the long-acting growth hormone yields superior efficacy compared to the administration of a daily dose of 0.24 mg / kg / week of somatropin.

8. The long-acting growth hormone or pharmaceutical preparation according to claim 7, wherein superior efficacy is measured as an annualized rate of height growth.

9. A long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 8, wherein the growth hormone deficiency is a growth hormone deficiency in children.

10. A long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 9, wherein the long-acting growth hormone is administered once a week or less.

11. A long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 10, wherein the time between two consecutive administrations is one week.

12. The long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 11, wherein the pharmaceutical preparation is a dried preparation.

13. The long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 11, wherein the pharmaceutical preparation is a liquid preparation.

14. Long-acting growth hormone is given by formula (Ia) or (Ib) 【Chemistry 1】 [In the formula, -D is the hGH moiety that is bonded to the rest of the molecule via an amine functional group. n is 0, 1, 2, 3, or 4. -X- is a chemical bond or spacer, =Y 1 ,=Y 5 It is independently selected from the group consisting of =O and =S, -Y 2 -, -Y 3 - is selected from the group consisting of -O- and -S-, -Y 4 - is -O-, -NR 5 - and -C(R 6 R 6a Selected from the group consisting of )-, -R 1 is a carrier, preferably a water-soluble PEG-based moiety comprising at least 40% PEG, -R 2 , -R 3 , -R 5 , -R 6 , -R 6a These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. -R 4 This is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. -W- is C 3～10 Cycloalkyl, 8-30 membered carbopolycyclyl, 3-10 membered heterocyclyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S- and -N(R 7 )- which may be interrupted by one or more groups selected from the group consisting of C 1～20 Selected from the group consisting of alkyl groups, -Nu is -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH, 【Chemistry 2】 A nucleophile selected from the group consisting of, -Ar- is, 【Transformation 3】 (In the formula, The dashed line indicates the binding of the prodrug to the rest of the body. -Z 1 - are -O-, -S- and -N(R 7 Selected from the group consisting of )-, -Z 2 - is -N(R 7 )-is) Selected from the group consisting of, -R 7 , -R 7a , -R 7b is -H, C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 [Selected independently from the group consisting of alkinyls] And, A long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 13, wherein the prodrugs of formulas (Ia) and (Ib) are optionally further substituted.

15. A long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 14, wherein the long-acting growth hormone is ACP-011.

16. A long-acting growth hormone or pharmaceutical preparation according to any one of claims 1 to 14, wherein the long-acting growth hormone is somapsitan.

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