Pharmaceutical compositions and uses thereof

Abstract

Provided herein is a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for once weekly subcutaneous administration, wherein the release half-life of SEQ ID NO: 2 is greater than about 100 hours.

Description

[0001] Cross-references This application claims the benefit of U.S. Provisional Patent Application No. 63 / 590,345, filed October 13, 2023, and U.S. Provisional Patent Application No. 63 / 638,538, filed April 25, 2024; the entire contents of each of these applications are incorporated herein by reference. Background Technology

[0002] By secreting parathyroid hormone (PTH), the parathyroid glands maintain blood calcium levels within a very narrow range (8-10 mg / dL in adults). Calcium stored in bones is released in response to PTH to support central nervous system function, vasoconstriction and muscle contraction, enzyme and hormone secretion, and blood clotting. Mechanistically, PTH increases calcium concentration by stimulating the production of the biologically active form of vitamin D in the kidneys, while simultaneously mobilizing calcium and phosphate from the bones, signaling to the kidneys to eliminate excess phosphate, and maximizing renal tubular reabsorption of calcium within the kidneys.

[0003] Hypoparathyroidism (hypo PT) is a rare condition characterized by insufficient production of PTH. Individuals with hypo PT excrete excessive calcium in their urine, have excessive phosphate in their blood, and exhibit abnormally low bone turnover. Prior to the FDA approval of NPS / Shire's Natpara® (rhPTH) in January 2015, hypoparathyroidism was one of the very few classic endocrine disorders not treated with hormone replacement therapy. Natpara® offers only modest efficacy compared to standard treatment consisting of high-dose calcium and vitamin D supplementation. Even so, the drug has been widely popular since its launch in 2015, indicating a significant unmet need in the treatment of hypo PT.

[0004] Because hypo PT is a rare disease, drugs developed for hypo PT benefit from orphan drug designation from the FDA and the European Medicines Agency (EMA). Various emerging competing products aim to restore PTH in a more physiological manner than Natpara®, primarily by normalizing serum calcium and reducing the long-term consequences of inadequate disease management. These competing products differ in their methods of normalizing PTH and their product portfolios vary considerably, including routes of administration, potency, dosing frequency, and therapeutic index. The compositions disclosed herein provide a once-weekly treatment for subjects with hypo PT that safely restores and maintains physiological PTH levels throughout the week, offering unique pharmacological benefits and significant convenience.

[0005] Hypo PT can be classified into primary and secondary diseases. Primary diseases occur when there is an intrinsic defect in the parathyroid glands (due to genetic causes). Hypo PT due to genetic causes is particularly rare, believed to account for less than 10% of all cases. Secondary or acquired diseases occur when previously functional parathyroid glands are impaired, destroyed, or ablated. Secondary diseases are currently the most common type, accounting for approximately 90% of all cases.

[0006] At least 75% of acquired hypotonic PT cases are caused by anterior neck surgery (i.e., total thyroidectomy or radical neck dissection for head and neck malignancies), as these surgeries may unintentionally or unavoidably remove or damage the parathyroid glands and / or their blood supply. Transient hypotonic PT is relatively common after thyroid surgery, estimated to occur in 7%–46% of thyroid surgeries. Transient hypotonic PT resolves within weeks or months postoperatively. Chronic hypotonic PT is rare, with an incidence of 0.9%–1.6% in experienced endocrinologists and high-volume surgical centers. However, the incidence has been reported as high as 6.6% after thyroid surgery, highlighting the importance of expertise and experience in avoiding permanent damage leading to hypotonic PT.

[0007] Following anterior neck surgery, the second most common acquired cause of hypo PT in adults is considered to be autoimmune disease. This disease can affect only the parathyroid glands or multiple endocrine glands. It is estimated that autoimmune-mediated diseases cause less than 10% of acquired hypo PT. Other secondary causes include rare infiltrative conditions due to metastatic disease or iron / copper overload, exposure to ionizing radiation, or those of unknown origin (idiopathic).

[0008] The estimated prevalence of hypo-PT in the United States ranges from 60,000 to 115,000 patients. The best estimate recommended by experts (based on large health plan claims databases) is 77,000 patients, of whom 58,793 are insured. Data for other regions are extremely limited, and based on literature, estimates range from 70,000 to 267,000 in Europe, 20,000 in Japan, and 30,000 in the rest of the world.

[0009] Chronic hypothyroidism (HPT) is a growing condition driven by the incidence and treatment of thyroid diseases, including cancer, particularly surgery. For example, the total number of thyroidectomies performed in the United States increased by 39% between 1996 and 2006, from 66,864 to 92,931. It is estimated that 150,000 thyroidectomies are now performed annually in the United States. The number of people potentially affected by HPT is growing. Because thyroid diseases affect women more than men, more than 70% of people with HPT are women.

[0010] Most people with calcium levels outside the normal physiological range will experience discomfort. Because calcium plays a vital role in nerve and muscle function, people with hypocalcemia may experience tingling or burning sensations in the extremities (paresthesia), muscle twitching, muscle pain, involuntary muscle contractions (tetany), dry / rough skin, difficulty concentrating or maintaining focus, anxiety, and / or depression. Severely low blood calcium levels can cause life-threatening laryngospasm, seizures, or arrhythmias, requiring emergency treatment with intravenous calcium. Serious long-term consequences of hypocalcemia (PT) can include nephrocalcinosis, impaired kidney function / chronic kidney disease, soft tissue calcium deposition, and bone hypermineralization.

[0011] Hypo PT is typically diagnosed through clinical history and laboratory tests. The hallmarks of this diagnosis are low / undetectable serum PTH levels, along with hypocalcemia (defined as total serum calcium below the lower limit of normal) and hyperphosphatemia. Levels of activated vitamin D and bone turnover markers are usually also in the lower limit of normal to significantly low ranges, with increased calcium excretion. Such laboratory findings can lead to a direct diagnosis of hypo PT in the context of recent neck surgery. However, cases of hypo PT can be very difficult to diagnose, especially when there is no known damage to the parathyroid glands.

[0012] There are no clear guidelines for the treatment of hypo PT, therefore treatment is based on experience and clinical judgment. The generally accepted main goal of chronic treatment is to keep serum total calcium (low to lower than normal), serum phosphorus (higher than normal), 24-hour urinary calcium excretion (<7.5 mmol / d), and calcium phosphate products (<4.4 mmol2 / L2) within acceptable ranges.

[0013] Standard treatment includes calcium, vitamin D metabolites, and sometimes thiazide diuretics. Recommended calcium supplements are calcium carbonate and calcium citrate, and the required amounts vary considerably (9-fold) among patients. 1,25(OH)2D3 (calcitriol) is an active metabolite of vitamin D and helps maintain serum calcium by improving intestinal calcium absorption efficiency. Calcitriol is also administered over a wide (8-fold) dosing range. Thiazide diuretics (benzothiadiazides) can also be used to treat hypo-PT by enhancing distal renal tubular calcium reabsorption.

[0014] While supplementing calcium and vitamin D to address calcium deficiency may sound simple, achieving good control is extremely difficult in reality. Most patients experience a rollercoaster of dosage levels, alternating between too high and too low. Furthermore, calcium and vitamin D supplements do not help restore the underlying PTH deficiency, which has therapeutic consequences.

[0015] Patients with hypoparathyroidism (PT) experience a heavy disease burden, significantly and negatively impacting their quality of life as well as the lives of their caregivers, family, and friends. NPS Pharmaceuticals conducted an epidemiological study of 374 patients called PARADOX to assess the clinical, social, and economic impacts of hypoparathyroidism. Data were collected using a 30-minute web-based tool developed based on feedback from clinical experts, the Hypoparathyroidism Association, and patients. This tool was primarily disseminated via email to members of the Hypoparathyroidism Association, including adults living in the United States who had had hypoparathyroidism for six months or more. Hadker et al. published their results in Endocrine Practice, with key highlights as follows: (i) 72% experienced more than 10 symptoms per day, with the most frequently reported symptoms being: (ii) Physical symptoms: fatigue (82%), muscle pain / cramps (78%), paresthesia (76%), tetany (70%), joint or bone pain (67%), and pain or weakness in the limbs (53%). (iii) Mood symptoms: anxiety (59%) and depression (53%) (iv) Cognitive symptoms: brain fog / mental fatigue (72%), inability to concentrate (65%), memory loss (61.5%), and sleep disturbances (57%). (v) 79% required hospitalization or emergency care. (vi) 45% reported that their lives were significantly disrupted. (vii) 85% reported being unable to perform household chores, and (viii) 20% experienced changes in employment status related to the disease.

[0016] Other publications have also confirmed the disease burden of hypo-PT. A cross-sectional study published by Arlt et al. in the European Journal of Endocrinology compared well-being and mood in 25 women with postoperative hypo-PT who underwent calcium and vitamin D stabilization therapy with 25 women with intact parathyroid function after thyroid surgery using a validated questionnaire. Hypo-PT patients had significantly higher overall complaint scores on the Geissen Discomfort List, von Zerssen Symptom List, and Symptom Checklist-90, and increased scores on subscales of anxiety, phobic anxiety, and their physical equivalents. Importantly, current standard treatments for hypo-PT have not restored well-being in these patients. Summary of the Invention

[0017] Prolonged release time of injected drugs is generally desirable to increase their duration of action or reduce their toxicity. Formulations that are readily soluble in the body are typically absorbed rapidly and provide a burst of available drug, rather than the more desirable gradual release of the pharmacologically active product.

[0018] Numerous attempts have been made to provide controlled-release and prolonged-release drug compounds, but previously disclosed techniques have failed to overcome all the technology-related challenges, such as achieving optimal extended release time, maximizing stability and efficacy, reducing toxicity, maximizing reproducibility of preparation, and eliminating unwanted physical, biochemical, or toxicological effects introduced by undesirable matrix materials. Therefore, there is a need for formulations that safely and effectively prolong the half-life of existing drugs and improve their dose-to-dose and patient-to-patient therapeutic index. This is crucial for drugs with a narrow therapeutic index (to distinguish between effective and toxic doses). PTH, very similar to insulin or thyroid hormones, is considered a drug that produces acute and chronic adverse consequences when calcium levels rise slightly beyond the physiological range.

[0019] Mechanisms for providing prolonged release and enhanced therapeutic index include isolating the molecule at the injection site or administering it as a prodrug derivative, where the prodrug derivative is designed to delay the onset of action and prolong the drug's half-life. The advantage of delayed onset is that it allows the prodrug to distribute systemically before its activation. Therefore, prodrug administration can eliminate complications caused by peak activity at administration and increase the therapeutic index of the parent drug.

[0020] Furthermore, receptor recognition and subsequent treatment of peptide and protein agonists are major pathways for the degradation of many peptide and protein-based drugs. Therefore, the binding of a peptide drug to its receptor generates biostimulation, but also initiates subsequent peptide / protein-induced pharmacological inactivation via enzymatic degradation of the peptide or protein. Thus, the use of prodrugs can also delay the duration of action of the administered drug, allowing for uniform systemic distribution before activation. This disclosure provides compositions and methods for safely prolonging the biological action of PTH while minimizing excessive effects shortly after administration.

[0021] In one aspect, this disclosure provides a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the release half-life of SEQ ID NO: 2 is greater than about 100 hours.

[0022] In another aspect, this disclosure provides a method for treating a subject suffering from hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject a dose of at least about 30 μg once weekly, wherein the dose comprises SEQ ID NO: 1.

[0023] In another aspect, this disclosure provides a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the pharmacokinetic profile of SEQ ID NO: 2 after administration of SEQ ID NO: 1 exhibits a peak-to-trough ratio of less than about 2 in plasma.

[0024] In another aspect, this disclosure provides a method for treating a subject with hypoparathyroidism, the method comprising: (a) determining the level of the subject's C-terminal telopeptide (CTX) after administering SEQ ID NO: 1 to the subject once a week, and (b) continuing to administer SEQ ID NO: 1 to the subject once a week, wherein the level of CTX is less than 900 pg / mL.

[0025] In another aspect, this disclosure provides a method for treating a subject with hypoparathyroidism, the method comprising: (a) determining the level of type I procollagen N-terminal propeptide (P1NP) in the subject after weekly administration of SEQ ID NO: 1, and (b) continuing to administer SEQ ID NO: 1 to the subject once weekly, wherein the level of P1NP in the subject is greater than about -50 μg / L.

[0026] Incorporation All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is expressly and individually indicated to be incorporated by reference. In the event of any publication, patent, or patent application incorporated by reference that contradicts the disclosure contained in this specification, this specification is intended to supersede and / or give precedence to any such contradictory material. Attached Figure Description

[0027] The novel features of the invention are set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings (also referred to herein as “figure” and “FIG.”) illustrating embodiments in which the principles of the invention are utilized, in which: Figure 1 The diagram illustrates the Phase 1 study design, objectives, and endpoints.

[0028] Figure 2 The figure shows the plasma concentrations of compounds 1 and 2 after weekly administration of compound 1 at different doses.

[0029] Figure 3 The figure illustrates the average change of CTX markers relative to baseline after weekly administration of compound 1 at different doses.

[0030] Figure 4 The figure illustrates the average change of the P1NP marker relative to baseline after weekly administration of compound 1 at different doses.

[0031] Figure 5 The possible mechanism of action of compound 1 and its conversion into compound 2 are illustrated.

[0032] Figure 6A The figure illustrates the maximum serum calcium level (E) after weekly administration of compound 1 at different doses and time points. max,adj ).

[0033] Figure 6B The figure shows the total serum calcium levels (AUEC0-τ, adj) after weekly administration of compound 1 at different doses and time points.

[0034] Figure 7 The figure illustrates endogenous PTH in healthy patients after weekly administration of compound 1 at different doses and time points. Detailed Implementation

[0035] The following description illustrates various exemplary configurations, methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0036] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure may be practiced without these details.

[0037] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications cited herein are incorporated herein by reference.

[0038] As used herein, the “effective” or “therapeutic effective” amount of a drug is a non-toxic amount sufficient to provide the intended effect. The effective amount will vary from person to person or even over time within the same person, depending on individual age and general condition, method of administration, etc. Therefore, it is not always possible to specify an exact effective amount. However, in any individual case, a person skilled in the art can determine the appropriate effective amount using routine experiments.

[0039] Unless the context clearly specifies otherwise, the singular forms “a / an”, “an”, and “the” as used in the specification and claims include plural references.

[0040] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. The organic bases from which the salt can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0041] As used in this article, “parenteral administration” refers to administration methods that are normally administered by injection, other than enteral and local administration, and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, and intrasternal injections and infusions.

[0042] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0043] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable,” meaning it is compatible with other components in the formulation and harmless to the recipient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and tragacanth oil. Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in pharmaceutical preparations.

[0044] In some implementations, the term "preventing" when associated with a disease or condition can refer to, in a statistical sample, the reduction of the occurrence of a disease or condition in a treated sample relative to an untreated control sample, or the delay of the onset of one or more symptoms of a disease or condition or a reduction of the severity of said one or more symptoms relative to an untreated control sample.

[0045] As used herein, the term "treatment" can include alleviating, reducing, or improving symptoms of a disease or condition; preventing additional symptoms; improving or preventing the underlying cause of symptoms; suppressing a disease or condition, such as halting its progression; reducing a disease or condition; causing a disease or condition to subside; reducing the condition caused by the disease or condition; or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0046] As used herein, the term "peak-to-valley ratio" refers to the ratio between the highest and lowest plasma concentrations of a compound (e.g., compound 2) at steady state.

[0047] As used herein, the terms “phosphate-buffered saline” or “PBS” refer to an aqueous solution containing sodium chloride and sodium phosphate. Different formulations of PBS are known to those skilled in the art, but for the purposes of this disclosure, the phrase “standard PBS” refers to a solution with a final concentration of 137 mM NaCl, 10 mM phosphate, 2.7 mM KCl, and a pH of 7.2–7.4.

[0048] As used in this article, the term "natural" or "naturally occurring" defines a state in which something exists in nature. "Natural amino acids" are amino acids that exist in nature through natural processes.

[0049] As used herein, the term "amino acid" encompasses any molecule containing both amino and carboxyl functional groups, wherein the amino and carboxyl groups are attached to the same carbon (α-carbon). The α-carbon may optionally have one or two other organic substituents. Amino acids can be designated by their three-letter code, single-letter code, or, in some cases, by the name of their side chain. For example, a non-canonical amino acid containing a cyclohexyl group attached to the α-carbon is referred to as "cyclohexane" or "cyclohexyl". For the purposes of this disclosure, designating an amino acid without specifying its stereochemistry is intended to cover the L-form or D-form, or racemic mixtures of amino acids. However, in the case where an amino acid is designated by its three-letter code (e.g., Lys) or single-letter code (e.g., K), such designation is intended to indicate the native L-form of the amino acid, while the D-form will be designated by adding a lowercase d before the three-letter code or single-letter code (i.e., dLys or dK). The designation of a particular amino acid as used herein is intended to cover native amino acids and any isotopically enriched derivatives of which have different molecular weights than native amino acids but possess equivalent physical and biological properties.

[0050] As used in this article, the term "hydroxy acid" refers to an amino acid that has been modified by replacing the α-carbon amino group with a hydroxyl group.

[0051] As used herein, the term “non-coding (non-standard) amino acid” encompasses any amino acid that is not an L-isomer of any of the following 20 amino acids: Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr.

[0052] A dipeptide is the result of linking an α-amino acid or α-hydroxy acid to another amino acid via a peptide bond.

[0053] As used herein, the term "chemical cleavage" encompasses, without further specification, non-enzymatic reactions that result in the breaking of covalent chemical bonds.

[0054] As used herein, an "acylated" amino acid is an amino acid that contains an acyl group, which is not naturally present in an amino acid, regardless of how it is generated. Exemplary methods for generating acylated amino acids and acylated peptides are known in the art and include acylation of the amino acid prior to incorporation into the peptide, or chemical acylation of the peptide after peptide synthesis. In some embodiments, the acyl group imparts to the peptide one or more of the following properties: (i) an extended circulating half-life, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) improved resistance to proteases such as DPP-IV, and (v) altered potency on PTH receptors.

[0055] "Bioactive peptide" refers to a peptide that can exert biological effects in vitro and / or in vivo. General references to peptides as used herein are intended to cover peptides having modified amino and carboxyl termini. For example, the amino acid sequences specifying standard amino acids are intended to cover standard amino acids at both the N-terminus and C-terminus, as well as the corresponding hydroxy acid at the N-terminus and / or the corresponding C-terminal amino acid modified to include an amide group (substituting the terminal carboxylic acid).

[0056] As used herein, an "acylated" amino acid is an amino acid that contains an acyl group, which is not naturally present in an amino acid, regardless of how it is generated. Exemplary methods for generating acylated amino acids and acylated peptides are known in the art and include acylation of the amino acid prior to incorporation into the peptide, or chemical acylation of the peptide after peptide synthesis. In some embodiments, the acyl group imparts to the peptide one or more of the following properties: (i) an extended circulating half-life, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) improved resistance to proteases such as DPP-IV, and (v) altered potency on PTH receptors.

[0057] As used herein, “alkylated” amino acids are amino acids that contain alkyl groups that are not naturally present in amino acids, regardless of how they are produced. Exemplary methods for producing alkylated amino acids and alkylated peptides are known in the art and include alkylating the amino acid before incorporating it into the peptide, or chemically alkylating the peptide after peptide synthesis.

[0058] As used in this article, a "receptor" is a molecule that recognizes a specific molecule and binds to it with high affinity, thereby producing a biological effect (direct or indirect) within or on the cells and / or tissues of a host organism. A "cell receptor" is a molecule on or within a cell that recognizes a specific molecule and binds to it, thereby producing a biological effect (direct or indirect) within the cell.

[0059] As used herein, the term "identity" refers to the similarity between two or more sequences. Identity is measured as a percentage by dividing the number of identical amino acid residues by the total number of residues and multiplying the result by 100. Thus, two identical copies of a sequence have 100% identity, while two sequences with amino acid deletions, additions, or substitutions relative to one another have a lower degree of identity. Those skilled in the art will recognize that several computer programs, such as those employing algorithms such as BLAST (Basic Local Alignment Search Tool, Altschul et al. (1993) J. Mol. Biol. 215:403-410), can be used to determine sequence identity.

[0060] As used in this article, "amino acid substitution" refers to the replacement of one amino acid residue with a different amino acid residue.

[0061] As used herein, the term “conserved amino acid substitution” is defined as an exchange within one of the following five groups: I. Small aliphatic nonpolar or micropolar residues: Ala, Ser, Thr, Pro, Gly; II. Polar residues with negative charges and their amides: Asp, Asn, Glu, Gln; III. Polar residues with positive charges: His, Arg, Lys; ornithine (Orn); IV. Large aliphatic nonpolar residues: Met, Leu, Ile, Val, Cys, leucine (Nle), homocysteine ​​(hCys); V. Large aromatic residues: Phe, Tyr, Trp, acetylphenylalanine, naphthylalanine (Nal).

[0062] As used herein, the general term “polyethylene glycol chain” or “PEG chain” refers to a mixture of condensation polymers of ethylene oxide and water, which are branched or linear, and are represented by the general formula H(OCH2CH2)kOH, where k is at least 2.

[0063] As used herein, the terms “miniPEG” or “OEG” define functionalized polyethylene compounds containing the following structures: .

[0064] As used herein, the term "polyglycolic" and similar terms refer to compounds whose native state is modified by linking polyethylene glycol chains. A "polyglycolic polypeptide" is a polypeptide having PEG chains covalently bound to it.

[0065] As used herein, a "connector" or "spacer" is a bond, molecule, or group of molecules that binds two separate entities together. A connector can provide optimal spacing between two entities, or it can further provide an unstable connection that allows the two entities to separate from each other. Unstable connections include photolyzable groups, acid-labile moieties, base-labile moieties, and enzyme-cleavable groups.

[0066] As used herein, a “dimer” is a complex comprising two subunits covalently bonded to each other via a linker. When used without any specific qualifier, the term “dimer” encompasses both homodimers and heterodimers. A homodimer contains two identical subunits, while a heterodimer contains two distinct subunits, although these subunits are substantially similar to each other.

[0067] As used in this article, the term "C1-C" n Alkyl (where n can be 1 to 6) refers to a branched or straight-chain alkyl group having one to a specified number of carbon atoms. Typical C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0068] As used in this article, the term "C16-C20 fatty acids" refers to the structure: -CO(CH2). 14-18 CH3, and the term "C16-C20 diacid" refers to the structure: -CO(CH2). 14-18 COOH, where the prefix "C16-C20" indicates the variable total number of carbons in the compounds it refers to. For example, C18 diacid indicates the structure: -CO(CH2). 16 COOH. As used herein, the general reference to acylated amino acids covers both amino acids with side chains acylated by fatty acids and amino acids with side chains acylated by diacids.

[0069] The physiological conditions disclosed herein are intended to include a temperature of approximately 35 to 40 °C and a pH of approximately 7.0 to approximately 7.4, and more typically include a pH of 7.2 to 7.4 and a temperature of 36 to 38 °C. Because physiological pH and temperature in the human body are strictly regulated within highly defined ranges, the rate of conversion of the dipeptide / drug complex (prodrug) to the drug will exhibit high in-patient and inter-patient reproducibility.

[0070] As used herein, the term “about” means 10% greater or less than the stated value or range, but is not intended to limit any value or range to this broader definition.

[0071] abbreviation Lowercase k = d-isomer of lysine γE = 1-isomer of γ-glutamic acid (miniPEG)2=COCH2OCH2CH2OCH2CH2NH COC16H32CO2H=(C18 diacid) (N-Me)G=sarcosine Uppercase K = 1-isomer of lysine compound In one aspect, this disclosure provides compound 1. In some cases, compound 1 is represented by the following chemical formula: k(γE-(miniPEG)2-γE-COC16H32CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE)-miniPEG)2-γE-COC16H32CO2H)-OH (SEQ ID NO: 1), wherein γE is the l-isomer of γ-glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC16H32CO2H is a C18 diacid; and (N-Me)G is sarcosine. In some cases, the compound is represented by PTH(1-33), dK-1(γE-2xOEG-γE-diacid C18), N(Me)GO, K33(γE-2xOEG-γE-diacid C18). In some cases, compound 2 is represented by SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH (SEQ ID NO: 2). In some cases, SEQ ID NO: 2 is formed by cleavage of SEQ ID NO: 1. In some cases, SEQ ID NO: 2 is formed by in vivo cleavage of SEQ ID NO: 1.

[0072] This disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present invention having sufficiently acidic, sufficiently basic, or both functional groups can react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those containing quaternary nitrogen, can form salts with suitable counterions (e.g., halides, such as bromides, chlorides, or fluorides, especially bromides).

[0073] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can be... Z -or E - It exists in the form (either cis or trans). Furthermore, some chemical entities can exist in a variety of tautomeric forms. Unless otherwise stated, the compounds described herein are intended to include all... Z -、 E - and tautomerism.

[0074] A "tautomer" is a molecule in which a proton may transfer from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds described herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium will exist between the tautomers. The exact proportions of the tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include: .

[0075] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, for example, in 2 H, 3 H, 11 C 13 C and / or 14 Enrichment at C content. In one particular embodiment, the compound is deuterated at at least one site. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby prolonging the duration of drug action.

[0076] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure disclosed herein but with hydrogen substituted by deuterium or tritium, or carbon substituted by... 13 C- or 14 All C-enriched carbon-substituted compounds are within the scope of this disclosure.

[0077] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may use isotopes such as, for example, deuterium (… 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Marking. Consider using... 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 I. Isotopic substitution. All isotopic variants of the compounds of this invention, whether or not radioactive, are covered within the scope of this invention.

[0078] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and the following synthetic methods are included only as non-limiting examples.

[0079] Deuterium-substituted compounds were synthesized using various methods described in the following literature: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0080] Deuterated starting materials are readily available and can be processed using the synthetic methods described herein for the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0081] The compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous compounds), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0082] The compounds described herein may exist in some cases as diastereomers, enantiomers, or other stereoisomers. Unless otherwise specified, the compounds presented herein include all diastereomers, enantiomers, and epimers, and suitable mixtures thereof. Separation of stereoisomers can be performed by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, JohnWiley And Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0083] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. In some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Additionally, the compounds described herein may be present in a non-solventized form or in a solvated form that forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0084] As used in this article, the term "prodrug" is defined as any compound that has been chemically modified before it exhibits its pharmacological effects.

[0085] Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable when administered orally, whereas the parent drug may not be. Prodrugs can help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be engineered as reversible drug derivatives to act as modifiers to enhance drug transport to site-specific tissues or increase drug retention within cells.

[0086] In some embodiments, the prodrug design increases the lipophilicity of the agent. In some embodiments, the prodrug design increases effective water solubility. See, for example, Fedorak et al. Am. J. Physiol. , 269:G210-218(1995); McLoed et al., Gastroenterol , 106:405-413 (1994); Hochhaus et al., Biomed. Chrom.,6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37,87 (1987); J. Larsen et al., Int. J. Pharmaceutics , 47, 103 (1988); Sinkula et al., J. Pharm. Sci ., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems ACS Symposium Series, Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design (American Pharmaceutical Association and Pergamon Press, 1987, all references are incorporated herein by reference for the purposes of this disclosure). According to another embodiment, this disclosure provides a method for producing compounds as defined above. These compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0087] The synthetic chemical transformations and methods used to synthesize the compounds described herein are known in the art, and include, for example, those described in the following literature: R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed.(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis (1995).

[0088] pharmaceutical preparations In one aspect, this disclosure provides a pharmaceutical composition comprising SEQ ID NO: 1. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly. In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the half-life of SEQ ID NO: 2 is greater than about 100 hours. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the release half-life of SEQ ID NO: 2 is greater than about 100 hours, and wherein the half-life of SEQ ID NO: 1 is greater than about 70 hours. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2. In some cases, SEQ ID NO: 1 is subsequently converted to SEQ ID NO: 2 in vivo. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 in vivo after cleavage. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 via intramolecular self-cleavage. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 after diketopiperazine cyclization. In some cases, SEQ ID NO: 1 is converted to SEQ ID NO: 2 in vivo after non-enzymatic cleavage. In some cases, the release half-life of SEQ ID NO: 2 is greater than about 130 hours. In some cases, the release half-life of SEQ ID NO: 2 is greater than about 140 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 140 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is approximately 160 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 180 hours. In some cases, the release half-life of SEQ ID NO: 2 is less than 160 hours.In some cases, the release half-life of SEQ ID NO: 2 is about 100 hours to about 500 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 100 hours to about 300 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 100 hours to about 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 100 hours to about 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 150 hours to about 500 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 150 hours to about 300 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 150 hours to about 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 150 hours to about 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 150 hours to about 180 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 150 hours to about 160 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 100 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 120 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 130 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 140 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 228 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 194 hours. In some cases, the release half-life of SEQ ID NO: 2 is about 185 hours. In some cases, the half-life of SEQ ID NO: 2 is about 100 hours to about 500 hours. In some cases, the half-life of SEQ ID NO: 2 is about 100 hours to about 300 hours. In some cases, the half-life of SEQ ID NO: 2 is about 100 hours to about 250 hours. In some cases, the half-life of SEQ ID NO: 2 is about 100 hours to about 200 hours. In some cases, the half-life of SEQ ID NO: 2 is about 150 hours to about 500 hours. In some cases, the half-life of SEQ ID NO: 2 is about 150 hours to about 300 hours. In some cases, the half-life of SEQ ID NO: 2 is about 150 hours to about 250 hours. In some cases, the half-life of SEQ ID NO: 2 is about 150 hours to about 200 hours. In some cases, the half-life of SEQ ID NO: 2 is about 150 hours to about 180 hours.In some cases, the half-life of SEQ ID NO: 2 is about 150 hours to about 160 hours. In some cases, the half-life of SEQ ID NO: 2 is about 100 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is about 120 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is about 130 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is about 140 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is about 228 hours. In some cases, the half-life of SEQ ID NO: 1 is about 60 hours. In some cases, the half-life of SEQ ID NO: 1 is about 70 hours. In some cases, the half-life of SEQ ID NO: 1 is about 80 hours. In some cases, the half-life of SEQ ID NO: 1 is about 85 hours. In some cases, the half-life of SEQ ID NO: 1 is about 90 hours. In some cases, the half-life of SEQ ID NO: 1 is about 95 hours. In some cases, the half-life of SEQ ID NO: 1 is about 100 hours. In some cases, the half-life of SEQ ID NO: 1 is greater than about 60 hours. In some cases, the half-life of SEQ ID NO: 1 is greater than about 70 hours. In some cases, the half-life of SEQ ID NO: 1 is greater than about 80 hours. In some cases, the half-life of SEQ ID NO: 1 is greater than about 85 hours. In some cases, the half-life of SEQ ID NO: 1 is greater than about 90 hours. In some cases, the half-life of SEQ ID NO: 1 is greater than about 95 hours. In some cases, the half-life of SEQ ID NO: 1 is less than about 120 hours. In some cases, the half-life of SEQ ID NO: 1 is less than about 100 hours. In some cases, the half-life of SEQ ID NO: 1 is shorter than the release half-life of SEQ ID NO: 2. In some cases, for the same dose, the half-life of SEQ ID NO: 1 is shorter than the release half-life of SEQ ID NO: 2. In some cases, the release half-life of SEQ ID NO: 1 is from about 60 hours to about 100 hours. In some cases, the release half-life of SEQ ID NO: 1 is from about 75 hours to about 120 hours. In some cases, the dose comprises a pharmaceutical composition, wherein the dose is from about 200 μg to 900 μg. In some cases, the dose comprises a pharmaceutical composition, wherein the dose is about 200 μg. In some cases, the dose comprises a pharmaceutical composition, wherein the dose is about 400 μg. In some cases, the dose comprises a pharmaceutical composition, wherein the dose is about 600 μg.In some cases, the dosage comprises a pharmaceutical composition, wherein the dosage is approximately 900 μg. In some cases, the time to peak concentration (t) of the drug in SEQ ID NO: 1 is specified. max The duration is at least approximately 35 hours. In some cases, SEQ ID NO: 1's t max For at least approximately 40 hours. In some cases, t of SEQ ID NO: 1 max For at least approximately 45 hours. In some cases, t of SEQ ID NO: 1 max Less than approximately 60 hours. In some cases, t of SEQ ID NO: 1 max Less than approximately 55 hours. In some cases, t of SEQ ID NO: 1 max Less than approximately 50 hours. In some cases, t of SEQ ID NO: 2 max For at least approximately 45 hours. In some cases, t of SEQ ID NO: 2 max For at least approximately 50 hours. In some cases, t of SEQ ID NO: 2 max For at least approximately 55 hours. In some cases, t of SEQ ID NO: 2 max For at least approximately 60 hours. In some cases, t of SEQ ID NO: 2 max For at least approximately 65 hours. In some cases, t of SEQ ID NO: 2 max For at least approximately 67 hours. In some cases, t of SEQ ID NO: 2 max Less than approximately 75 hours. In some cases, t of SEQ ID NO: 2 max Less than approximately 70 hours. In some cases, t of SEQ ID NO: 2 max Less than approximately 65 hours. In some cases, t of SEQ ID NO: 2 max Less than approximately 60 hours. In some cases, t of SEQ ID NO: 2 max Less than approximately 55 hours. In some cases, t of SEQ ID NO: 1 max For at least approximately 35 hours, and t of SEQ ID NO: 2 maxThe AUC is at least about 45 hours. In some cases, for a dose containing about 200 μg SEQ ID NO: 2, the AUC of SEQ ID NO: 2 is at least about 100 hours. In some cases, for a dose containing about 400 μg SEQ ID NO: 2, the AUC of SEQ ID NO: 2 is at least about 180 hours. In some cases, for a dose containing about 600 μg SEQ ID NO: 2, the AUC of SEQ ID NO: 2 is at least about 320 hours. In some cases, for a dose containing about 900 μg SEQ ID NO: 2, the AUC of SEQ ID NO: 2 is at least about 420 hours. In some cases, the dosage may be as described in other parts of this document. In some cases, the pharmaceutical composition also contains pharmaceutically acceptable excipients. In some cases, the half-life is a cyclic half-life. In some cases, the half-life is a cyclic half-life in the subject. In some cases, the release half-life is the time it takes for the concentration or amount of a compound in the object to decrease by exactly half (50%).

[0089] In some implementations, the release half-life (t½) is the time it takes for the concentration or amount of the drug (e.g., SEQ ID NO: 2) in the subject to decrease by exactly half (50%).

[0090] In some implementations, compound 1 is considered a prodrug. In some cases, compound 2 is considered an active drug. In some cases, compound 2 is an active drug formed from compound 1.

[0091] In some embodiments, the conjugate is represented by ABQ, where ABQ is k(γE-(miniPEG)2-γE-COC16H32CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH. In some cases, AB is a self-cleaving dipeptide. In some cases, AB is represented by k(γE-(miniPEG)2-γE-COC16H32CO2H)(N-Me). In some cases, Q is represented by SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH. In some cases, ABQ is converted to AB and Q. In some cases, AB dissociates via a cyclization pathway, where AB forms a cyclic compound, leaving Q (e.g., compound 2). In some cases, cyclization occurs at physiological pH. In other cases, cyclization occurs at approximately pH 7.4. In some cases, the chemical cleavage half-life (t) of AB from ABQ is [not specified]. 1 / 2 The chemical cleavage half-life can be measured as described in WO2021242756A2 (PCT / US2021 / 034055) and US20230285578A1. In some cases, the chemical cleavage half-life is measured in standard PBS solution under physiological conditions.

[0092] In some embodiments, compound 1 is derived from (SEQ ID NO: 1) express.

[0093] In some embodiments, compound 2 (SEQ ID NO: 2) is composed of express.

[0094] In some embodiments, this document provides compositions comprising a therapeutically effective amount of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, or a pharmaceutically acceptable salt of any of them (also referred to herein as a “pharmaceutical”).

[0095] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers (including excipients and adjuvants) that facilitate the processing of the pharmaceutical agent into a pharmaceutical formulation. The appropriate formulation depends on the chosen route of administration. An overview of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins, 1999).

[0096] The compositions and methods disclosed herein can be used to treat individuals in need. In some embodiments, the individual is a mammal such as a human or a non-human mammal. When administered to an animal (such as a human), the composition or agent is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or physiologically buffered saline) or other solvents or mediators (such as glycols, glycerols, oils (such as olive oil), or injectable organic esters). In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (such as injection or implantation routes such as those bypassing transport or diffusion across the epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, the excipient may be selected to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules, granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems, such as skin patches. The composition may also be present in solutions suitable for topical application, such as eye drops.

[0097] Pharmaceutically acceptable excipients may contain physiologically acceptable agents that function, for example, to stabilize, increase solubility, or increase the absorption of compounds (such as pharmaceuticals). Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable excipients (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix, which may contain compounds such as those of the present invention incorporated therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0098] The pharmaceutical composition can be administered to the target via any of a variety of routes of administration, including, for example, oral administration, such as drenches, tablets, capsules (including spray capsules and gelatin capsules), pellets, powders, granules, or pastes for application to the tongue; absorption through the oral mucosa, such as sublingually; via the anus, rectum, or vagina, such as in the form of vaginal suppositories, creams, or foams; parenteral administration, including intramuscular, intravenous, subcutaneous, or intrathecal administration, such as in the form of sterile solutions or suspensions; nasal administration; intraperitoneal administration; subcutaneous administration; percutaneous administration, such as in the form of patches for application to the skin; and topical administration, such as in the form of creams, ointments, or sprays for application to the skin, or in the form of eye drops. The compound can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water.

[0099] The pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension, or emulsion, such as a microemulsion. The excipients described herein are exemplary and do not constitute a limitation. An effective amount, or therapeutically effective amount, refers to the amount of one or more pharmaceutical agents administered to a subject in a single dose or as part of a series of doses that is effective in producing the desired therapeutic effect.

[0100] In general, appropriate assays and methods suitable for the treated condition can be used to monitor the efficacy of treatment in a subject. These assays are familiar to those skilled in the art and are described herein. The pharmacokinetics of a drug or one or more metabolites administered to a subject can be monitored by measuring the levels of the drug or metabolites in the subject's biological fluids (e.g., blood, blood fractions (e.g., serum), and / or urine, and / or other biological samples or tissues from the subject). Any method practiced in the art and described herein for detecting said agents can be used to measure the levels of the drug or metabolites during treatment.

[0101] The dosage of the pharmaceutical agents described herein for the treatment of a disease or condition may depend on the subject's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, overall health status, and age, sex, and weight, as well as other factors obvious to a person skilled in the medical field. The pharmaceutical composition may be administered in a manner suitable for the disease to be treated, as determined by a person skilled in the medical field. In addition to the factors described herein and above related to the use of pharmaceutical agents for the treatment of a disease or condition, the appropriate duration and frequency of administration of the pharmaceutical agent may be determined or adjusted based on factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the agent can generally be determined using experimental models and / or clinical trials. The optimal dosage may depend on the subject's body mass, weight, or blood volume. Generally, the minimum dose sufficient to provide effective treatment is preferred. The design and execution of preclinical and clinical studies of the pharmaceutical agents described herein (including when used for prophylactic benefit) are entirely within the skill of a person skilled in the relevant field. When two or more pharmaceutical agents are administered to treat a disease or condition, the optimal dosage of each agent may differ, such as being lower than the dosage when either agent is administered alone as a monotherapy. In certain specific embodiments, the two agents may act synergistically or additively, and either agent may be used at a lower dose than when administered alone. The daily dose may be, for example, from about 0.01 mg / kg to 100 mg / kg body weight, such as about 0.1 to 1 mg / kg body weight, about 1 to 10 mg / kg body weight, about 10-50 mg / kg body weight, or about 50-100 mg / kg body weight. In other embodiments, the daily dose may be from about 0.01 mg / kg to 1000 mg / kg body weight, about 100-500 mg / kg body weight, or about 500-1000 mg / kg body weight. The optimal daily or per-course dose may vary depending on the disease or condition being treated and may also vary depending on the route of administration and treatment regimen.

[0102] Pharmaceutical compositions containing pharmaceutical agents can be formulated using techniques conventionally practiced in the art in a manner suitable for delivery methods. The compositions can be in the form of solids (e.g., tablets, capsules), semi-solids (e.g., gels), liquids, or gases (e.g., aerosols). In other embodiments, the pharmaceutical composition is administered via bolus infusion.

[0103] Pharmaceutically acceptable excipients are well-known in the pharmaceutical field and, for example, Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy ( Described in Gennaro, 21st Edition, Mack Pub. Co., Easton, PA (2005). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc., may be provided in the pharmaceutical composition. Additionally, antioxidants and suspending agents may be used. Generally, the choice of excipient type is based on the route of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be formulated into lyophilized products using one or more suitable excipient solutions via lyophilization or otherwise to dissolve and / or dilute the pharmaceutical agent in the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated in liposomes using techniques known and practiced in the art. In certain specific embodiments, the pharmaceutical agent is not formulated in liposomes for application to stents used to treat highly (but not completely) occluded arteries. Pharmaceutical compositions may be formulated for any suitable route of administration described herein and in the art.

[0104] Pharmaceutical compositions, such as those for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods, may be in liquid form. Liquid pharmaceutical compositions may include one or more of the following: sterile diluents such as water, saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspension media, polyethylene glycol, glycerin, propylene glycol, or other solvents; antibacterial agents; antioxidants; chelating agents; buffers; and agents for adjusting tension such as sodium chloride or dextran. Parenteral compositions may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological saline is preferred, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, for the treatment of ophthalmic conditions or diseases, the liquid pharmaceutical composition may be administered to the eye as eye drops. The liquid pharmaceutical composition may be delivered orally.

[0105] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to prepare tablets, powders, granules, or capsules, and, if desired, can be used in combination with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. The pharmaceutical agent can be formulated with a buffer to protect the compound from the low pH of the gastric environment and / or to provide an enteric coating. Pharmaceutical agents included in a pharmaceutical composition can be formulated with a flavoring agent (e.g., in liquid, solid, or semi-solid dosage forms) and / or with an enteric coating for oral delivery.

[0106] Pharmaceutical compositions comprising any of the agents described herein can be formulated for sustained or slow release, also known as timed or controlled release. Such compositions are typically prepared using well-known techniques and administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation at a desired target site. Sustained-release formulations may contain compounds dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-controlled membrane. Excipients used in such formulations are biocompatible and may also be biodegradable; preferably, the formulation provides a relatively constant level of release of the active ingredient. The amount of agent contained in a sustained-release formulation depends on the implantation site, release rate, and expected duration of release, as well as the nature of the condition, disease, or ailment to be treated or prevented.

[0107] In some embodiments, the pharmaceutical composition containing the agent is formulated for transdermal, intradermal, or topical application. The composition can be applied using syringes, bandages, transdermal patches, inserts, or syringe-like applicators in the form of powder / talc or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, or pastes. This is preferably in the form of a controlled-release or sustained-release formulation, applied topically or injected directly into the skin near or within the area to be treated (e.g., intradermal or subcutaneous). The active composition can also be delivered via iontophoresis. Antiseptics can be used to prevent the growth of fungi and other microorganisms. Suitable antiseptics include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzyl chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenethyl alcohol, thimerosal, and combinations thereof.

[0108] Pharmaceutical compositions containing pharmaceutical agents can be formulated into emulsions for topical application. The emulsion contains a liquid distributed within a bulk of a second liquid. The emulsion can be an oil-in-water emulsion or an oil-in-water emulsion. Either or both of the oil and aqueous phases may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily, pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or moisturizing agent.

[0109] Ointments and creams can be formulated, for example, with an aqueous or oil-based base, in which suitable thickeners and / or gelling agents are added. Lotions can be formulated with an aqueous or oil-based base and typically also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Liquid sprays can be delivered by pressurized packaging, such as through specially shaped closures. Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsions, microemulsions, or foam emulsion systems.

[0110] In some embodiments, the pharmaceutical agents described herein can be formulated as inhalers. Inhalation methods can deliver the drug directly to the airways. The agents can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The agents can be formulated using solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery as liquid aerosols or inhalable dry powder. Liquid aerosol formulations are optionally primarily atomized into particle sizes that can be delivered to the terminal bronchioles and respiratory bronchioles. Liquid aerosols and inhalable dry powder formulations are preferably delivered through the entire bronchial canal to the terminal bronchioles and ultimately to the parenchymal tissue.

[0111] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device (such as a jet injector, vibrating perforated plate, or ultrasonic nebulizer), preferably a device that allows the formation of aerosol particles with a median average diameter primarily between 1 and 5 μm. Furthermore, the formulation preferably has a balanced osmotic pressure ionic strength and chloride concentration, and a minimum aerosolizable volume capable of delivering an effective dose of the drug. Additionally, the aerosolized formulation preferably does not negatively affect airway function and does not cause undesirable side effects.

[0112] Suitable aerosol atomizing devices for administering the aerosol formulations described herein include, for example, jet injectors, vibrating perforated plates, ultrasonic nebulizers, and electrically powered dry powder inhalers, which are capable of atomizing the formulation into aerosol particles primarily in the 1-5 μm size range. In this application, "primarily" means that at least 70%, but preferably more than 90%, of all generated aerosol particles are in the 1-5 μm range. Jet injectors operate by breaking a liquid solution into aerosol droplets using air pressure. Vibrating perforated plate nebulizers operate by using an acoustic vacuum generated by a rapidly vibrating perforated plate to force solvent droplets through the plate. Ultrasonic nebulizers operate by shearing the liquid into small aerosol droplets using piezoelectric crystals. A variety of suitable devices are available, including, for example, the AeroNeb™ and AeroDose™ vibrating perforated plate nebulizers (AeroGen, Inc., Sunnyvale, California), the Sidestream® nebulizer (Medic-Aid Ltd., West Sussex, England), the Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and the Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0113] In some embodiments, the agent may be formulated with an oily matrix or ointment to form a semi-solid composition having the desired shape. In addition to the agent, these semi-solid compositions may also contain dissolved and / or suspended systems of bactericides, preservatives, and / or buffers. The petrolatum component that may be included may be any paraffin wax with a viscosity ranging from mineral oils doped with isobutylene, colloidal silica, or stearates to paraffin wax. The absorbent matrix may be used with the oily system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, lanolin alcohol, low HLB (hydrophobic-oleophobic balance) emulsifiers, and a variety of ionic and nonionic surfactants (used alone or in combination).

[0114] By adding time-release additives (such as polymer structures and matrices) available in the art, controlled or sustained release transdermal or topical formulations can be achieved. For example, the composition can be administered using a hot-melt extruded article (such as a bioadhesive hot-melt extruded film). The formulation may include cross-linked polycarboxylic acid polymer formulations. The cross-linking agent may be present in an amount that provides sufficient adhesion to allow the system to remain attached to the surface of target epithelial or endothelial cells for a sufficient time to allow the desired release of the compound.

[0115] Inserts, transdermal patches, bandages, or articles may contain polymer mixtures or coatings that provide the release of a drug at a constant rate over an extended period of time. In some embodiments, the article, transdermal patch, or insert contains a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which can be mixed with a water-insoluble polymer to increase the durability of the insert and prolong the release of the active ingredient.

[0116] Transdermal devices (insertions, patches, bandages) may also contain water-insoluble polymers. Rate-controlled polymers can be used to apply to sites where release can be achieved through pH changes. These rate-controlled polymers can be applied using a continuous coating film during the spraying and drying process with the active compound. In one embodiment, a coating formulation is used to coat pellets containing the active ingredient, which are compressed to form a solid, biodegradable insert.

[0117] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. For example, sustained-release gels and compounds can be incorporated into a polymer matrix (such as a hydrophobic polymer matrix). Examples of polymer matrices include microparticles. Microparticles can be microspheres, and the core can have a different material than the polymer shell. Alternatively, the polymer can be cast into a thin slab or film, a powder produced by milling or other standard techniques, or a gel (such as a hydrogel). Polymers can also be in the form of coatings or as part of bandages, stents, catheters, vascular grafts, or other devices to facilitate drug delivery. The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0118] Kits are provided that contain unit doses (typically oral or injectable) of one or more of the agents described herein. Such kits may include containers containing unit doses, informational packaging inserts describing the use of the drug in treating diseases and associated benefits, and optionally, appliances or devices for delivering the composition.

[0119] In some embodiments, the kit includes a means for administering compound 1 (SEQ ID NO: 1) or a pharmaceutical composition containing compound 1 to a patient. The kit may also include various containers, such as vials, tubes, bottles, etc. Preferably, the kit will also include instructions for use. In some cases, the kit's means is an aerosol dispensing device, wherein the composition is pre-packaged within the aerosol device. In some cases, the kit includes a syringe and a needle, and in some embodiments, compound 1 or a pharmaceutical composition containing compound 1 is pre-packaged within a syringe or injection pen, using a small-gauge needle, such as a needle with a size of 29-31.

[0120] In some embodiments, the pharmaceutical composition comprising SEQ ID NO: 1 is suitable for subcutaneous administration. In some cases, the pharmaceutical composition comprising SEQ ID NO: 1 is suitable for subcutaneous administration once weekly.

[0121] In some embodiments, the pharmaceutical composition comprises compound 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the pharmacokinetic profile of compound 2 exhibits a peak-to-trough ratio of less than about 2 in plasma after administration of compound 2. In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the pharmacokinetic profile of SEQ ID NO: 2 exhibits a peak-to-trough ratio of less than about 2 in plasma after administration of SEQ ID NO: 1. In some cases, the peak-to-trough ratio in plasma is less than about 1.8. In some cases, the peak-to-trough ratio in plasma is less than about 1.6. In some cases, the peak-to-trough ratio in plasma is greater than about 1.1. In some cases, the peak-to-trough ratio in plasma is greater than about 1.2. In some cases, the peak-to-trough ratio in plasma is about 1.3. In some cases, the peak-to-trough ratio in plasma is about 1.4. In some cases, the peak-to-trough ratio in plasma is about 1.5. In some cases, the peak-to-trough ratio in plasma is about 1.6. In some cases, the peak-to-trough ratio in plasma is about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.9. In some cases, the peak-to-trough ratio in plasma is about 2. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.6. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.5. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.4. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.3. In some cases, the peak-to-trough ratio in plasma is about 1.1 to about 1.2. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.6. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.5. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.4. In some cases, the peak-to-trough ratio in plasma is about 1.2 to about 1.3. In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 1.6. In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 1.5.In some cases, the peak-to-trough ratio in plasma is about 1.3 to about 1.4. In some cases, the peak-to-trough ratio in plasma is about 1.4 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.4 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.4 to about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.4 to about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.4 to about 1.6. In some cases, the peak-to-trough ratio in plasma is about 1.4 to about 1.5. In some cases, the peak-to-trough ratio in plasma is about 1.5 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.5 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.5 to about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.5 to about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.5 to about 1.6. In some cases, the peak-to-trough ratio in plasma is about 1.6 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.6 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.6 to about 1.8. In some cases, the peak-to-trough ratio in plasma is about 1.6 to about 1.7. In some cases, the peak-to-trough ratio in plasma is about 1.7 to about 2. In some cases, the peak-to-trough ratio in plasma is about 1.7 to about 1.9. In some cases, the peak-to-trough ratio in plasma is about 1.7 to about 1.8.

[0122] In some cases, the peak-to-trough ratio is measured at steady state after subcutaneous administration of the pharmaceutical composition. In some cases, steady state is the time point at which the input mass of compound 2 equals the mass eliminated from the body by clearance during any unit of time. In some cases, steady state is the time point at which the input mass of compound 2 equals the mass eliminated from the body by clearance 300 hours prior.

[0123] In some cases, the peak-to-trough ratio (PKR) is measured approximately 250 hours after subcutaneous administration of the drug composition. In some cases, the PKR is measured approximately 200 hours after subcutaneous administration of the drug composition. In some cases, the PKR is measured approximately 48 hours after subcutaneous administration of the drug composition. In some cases, subcutaneous administration is performed by subcutaneous injection. In some cases, subcutaneous administration is performed using a pen device. In some cases, administration is performed on non-human primates. In some cases, administration is performed on monkeys. In some cases, administration is performed on mice. In some cases, administration is performed on humans.

[0124] In some embodiments, a pharmaceutical composition is provided wherein the disclosed compound 1 (SEQ ID NO: 1) is selected to provide an optimized level of compound 2 (SEQ ID NO: 2) in the patient's blood / serum / plasma. In some embodiments, a pharmaceutical composition is provided wherein the disclosed compound 1 (SEQ ID NO: 1) is selected to provide an optimized level of compound 2 (SEQ ID NO: 2) in the subject's plasma. In some cases, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein when a dose comprising SEQ ID NO: 1 is administered to the subject, the maximum plasma concentration (C0) of SEQ ID NO: 2 is... max The concentration is up to about 6 (nmol / L), with doses ranging from 200 μg to 900 μg. Dosages may be as described elsewhere in this document. In some cases, SEQ ID NO: 2 is formed by cleaving SEQ ID NO: 1.

[0125] In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 0.4 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 0.6 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 0.8 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.2 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.3 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.4 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.5 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.6 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... maxThe concentration is at least approximately 1.7 nmol / L. In some cases, the maximum plasma concentration (C) is... max The concentration is at least about 1.8 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 1.9 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.1 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.2 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.3 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.4 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.5 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.6 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.7 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 2.8 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration was at least about 2.9 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 was [missing value]. max The concentration is at least about 3.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 3.1 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at least about 3.2 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at most about 5.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... maxThe concentration is at most about 4.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at most about 3.9 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is higher. max The maximum plasma concentration (C) is approximately 3.8 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [not specified]. max The maximum plasma concentration (C) is approximately 3.7 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The concentration is at most about 3.6 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The maximum plasma concentration (C) is approximately 3.5 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The maximum plasma concentration (C) is approximately 3.4 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The concentration is at most about 3.3 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The maximum plasma concentration (C) is approximately 3.2 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The concentration is at most about 3.1 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at most about 3.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration is at most about 2.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration ranges from approximately 0.6 (nmol / L) to 4.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The concentration ranges from approximately 0.8 (nmol / L) to 3.2 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The concentration ranges from approximately 0.8 (nmol / L) to 2.4 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. max The concentration ranges from approximately 0.8 (nmol / L) to 1.3 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing value]. maxThe concentration is approximately 0.8 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The concentration was approximately 1.3 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 was [missing value]. max The concentration was approximately 2.4 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 2 was... max The concentration was approximately 3.2 nmol / L.

[0126] In some embodiments, the pharmaceutical composition comprises SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the maximum plasma concentration (C) of SEQ ID NO: 1 is [missing information]. max The concentration is at least about 2.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 3.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 4.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 5.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 6.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 7.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 8.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 9.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 10.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 11.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 12.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 13.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is...max The concentration is at least about 14.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 15.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 16.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 17.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at most about 20.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO:1 is higher. max The concentration is at least approximately 19.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least approximately 19.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 18.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 17.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 16.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 15.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least approximately 14.0 nmol / L. In some cases, the maximum plasma concentration (C) of SEQ ID NO:1 is... max The concentration is at least about 13.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 12.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 11.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 10.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... maxThe concentration is at least about 9.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 8.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 7.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 6.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 5.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 4.0 (nmol / L). In some cases, the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at least about 3.0 (nmol / L). In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is at least about 4. In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is at most about 6. In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4. In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4.2. In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 5.4. In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 5.5. In some cases, the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4 to about 6.

[0127] Treatment In one aspect, this disclosure provides a method for treating a subject suffering from hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject a dose of at least about 30 micrograms (μg) once weekly, wherein the dose comprises SEQ ID NO: 1. In some embodiments, a method for treating a subject suffering from hypoparathyroidism, osteoporosis, or osteopenia is provided, the method comprising administering to the subject a dose of at least about 30 μg once weekly, wherein the dose comprises a pharmaceutical composition containing SEQ ID NO: 1. In some embodiments, a method for treating a subject suffering from hypoparathyroidism is provided, the method comprising administering to the subject a dose of at least about 30 μg once weekly, wherein the dose comprises a pharmaceutical composition containing SEQ ID NO: 1. In some embodiments, a method for treating a subject suffering from hypoparathyroidism is provided, the method comprising administering to the subject a dose of at least about 30 μg once weekly, wherein the dose comprises a pharmaceutical composition containing SEQ ID NO: 1, and wherein the release half-life of SEQ ID NO: 2 is greater than about 100 hours. In some cases, the dose is at least about 50 μg. In some cases, the dose is at least about 100 μg. In some cases, the dose is at least about 200 μg. In some cases, the dose is at least about 300 μg. In some cases, the dose is at least about 400 μg. In some cases, the dose is at least about 500 μg. In some cases, the dose is at least about 600 μg. In some cases, the dose is at most about 1000 µg. In some cases, the dose is at most about 900 µg. In some cases, the dose is at most about 700 µg. In some cases, the dose is at most about 600 µg. In some cases, the dose is at most about 500 µg. In some cases, the dose is at most about 460 μg. In some cases, the dose is at most about 400 μg. In some cases, the dosage is about 50 μg, about 150 μg, about 200 μg, about 300 μg, about 400 μg, about 460 μg, about 600 μg, or about 900 μg. In some cases, the dosage is about 50 μg. In some cases, the dosage is about 150 μg. In some cases, the dosage is about 200 μg. In some cases, the dosage is about 300 μg. In some cases, the dosage is about 400 μg. In some cases, the dosage is about 460 μg. In some cases, the dosage is about 600 μg. In some cases, the dosage is about 900 μg. In some cases, the dosage is less than about 1000 μg. In some cases, the dosage is less than about 900 μg. In some cases, the dosage is less than 600 μg. In some cases, the dosage is from about 30 μg to 1000 μg. In some cases, the dosage is from about 30 μg to 900 μg.In some cases, the dosage is approximately 30 μg to 800 μg. In some cases, the dosage is approximately 30 μg to 700 μg. In some cases, the dosage is approximately 30 μg to 600 μg. In some cases, the dosage is approximately 30 μg to 500 μg. In some cases, the dosage is approximately 30 μg to 400 μg. In some cases, the dosage is approximately 30 μg to 300 μg. In some cases, the dosage is approximately 30 μg to 200 μg. In some cases, the dosage is approximately 30 μg to 100 μg. In some cases, the dosage is approximately 30 μg to 50 μg. In some cases, the dosage is approximately 50 μg to 1000 μg. In some cases, the dosage is approximately 50 μg to 900 μg. In some cases, the dosage is approximately 50 μg to 800 μg. In some cases, the dosage is approximately 50 μg to 700 μg. In some cases, the dosage is approximately 50 μg to 600 μg. In some cases, the dosage is approximately 50 μg to 500 μg. In some cases, the dosage is approximately 50 μg to 460 μg. In some cases, the dosage is approximately 50 μg to 400 μg. In some cases, the dosage is approximately 50 μg to 300 μg. In some cases, the dosage is approximately 50 μg to 200 μg. In some cases, the dosage is approximately 50 μg to 100 μg. In some cases, the dosage is approximately 50 μg to 75 μg. In some cases, the dosage is approximately 100 μg to 1000 μg. In some cases, the dosage is approximately 100 μg to 900 μg. In some cases, the dosage is approximately 100 μg to 800 μg. In some cases, the dosage is approximately 100 μg to 700 μg. In some cases, the dosage is approximately 100 μg to 600 μg. In some cases, the dosage is approximately 100 μg to 500 μg. In some cases, the dosage is approximately 100 μg to 460 μg. In some cases, the dosage is approximately 100 μg to 400 μg. In some cases, the dosage is approximately 100 μg to 300 μg. In some cases, the dosage is approximately 100 μg to 200 μg. In some cases, the dosage is approximately 100 μg to 100 μg. In some cases, the dosage is approximately 100 μg to 75 μg. In some cases, the dosage is approximately 200 μg to 1000 μg. In some cases, the dosage is approximately 200 μg to 900 μg. In some cases, the dosage is approximately 200 μg to 800 μg. In some cases, the dosage is approximately 200 μg to 700 μg. In some cases, the dosage is approximately 200 μg to 600 μg. In some cases, the dosage is approximately 200 μg to 500 μg. In some cases, the dosage is approximately 200 μg to 460 μg. In some cases, the dosage is approximately 200 μg to 400 μg.In some cases, the dosage is approximately 200 μg to 300 μg. In some cases, the dosage is approximately 300 μg to 1000 μg. In some cases, the dosage is approximately 300 μg to 900 μg. In some cases, the dosage is approximately 300 μg to 800 μg. In some cases, the dosage is approximately 300 μg to 700 μg. In some cases, the dosage is approximately 300 μg to 600 μg. In some cases, the dosage is approximately 300 μg to 500 μg. In some cases, the dosage is approximately 300 μg to 460 μg. In some cases, the dosage is approximately 300 μg to 400 μg. In some cases, the dosage is approximately 400 μg to 1000 μg. In some cases, the dosage is approximately 400 μg to 900 μg. In some cases, the dosage is approximately 400 μg to 800 μg. In some cases, the dosage is approximately 400 μg to 700 μg. In some cases, the dosage is approximately 400 μg to 600 μg. In some cases, the dosage is approximately 400 μg to 500 μg. In some cases, the dosage is approximately 400 μg to 460 μg. In some cases, the dosage is approximately 460 μg to 1000 μg. In some cases, the dosage is approximately 460 μg to 900 μg. In some cases, the dosage is approximately 460 μg to 800 μg. In some cases, the dosage is approximately 460 μg to 700 μg. In some cases, the dosage is approximately 460 μg to 600 μg. In some cases, the dosage is approximately 460 μg to 500 μg. In some cases, the dosage is approximately 500 μg to 1000 μg. In some cases, the dosage is approximately 500 μg to 900 μg. In some cases, the dosage is approximately 500 μg to 800 μg. In some cases, the dosage is approximately 500 μg to 700 μg. In some cases, the dosage is approximately 500 μg to 600 μg. In some cases, the dosage is approximately 600 μg to 1000 μg. In some cases, the dosage is approximately 600 μg to 900 μg. In some cases, the dosage is approximately 600 μg to 800 μg. In some cases, the dosage is approximately 600 μg to 700 μg. In some cases, the dosage is approximately 700 μg to 1000 μg. In some cases, the dosage is approximately 700 μg to 900 μg. In some cases, the dosage is approximately 700 μg to 800 μg. In some cases, the method is used to treat hypoparathyroidism in patients with need. In some cases, the method is used to treat osteoporosis or osteopenia in patients with need. In some cases, the dose is administered once a week for 2 weeks. In some cases, the dose is administered once a week for 3 weeks. In some cases, the dose is administered once a week for 4 weeks.In some cases, the dose is administered weekly for 5 weeks. In some cases, the dose is administered weekly for 6 weeks. In some cases, the dose is administered weekly for 7 weeks. In some cases, the dose is administered weekly for 8 weeks. In some cases, the dose is administered weekly for 9 weeks. In some cases, the dose is administered weekly for 10 weeks. In some cases, the dose is administered weekly for 11 weeks. In some cases, the dose is administered weekly for 12 weeks. In some cases, the dose is administered weekly for 13 weeks. In some cases, the dose is administered weekly for 14 weeks. In some cases, the dose is administered weekly for 15 weeks. In some cases, the dose is administered weekly for 16 weeks. In some cases, the dose is administered weekly for 17 weeks. In some cases, the dose is administered weekly for 18 weeks. In some cases, the dose is administered weekly for 19 weeks. In some cases, the dose is administered weekly for 20 weeks. In some cases, the dose is administered weekly for 21 weeks. In some cases, the dose is administered weekly for 22 weeks. In some cases, the dose is administered weekly for 23 weeks. In some cases, the dose is administered weekly for 24 weeks. In some cases, the dose is administered weekly for 25 weeks. In some cases, the dose is administered weekly for 26 weeks. In some cases, the dose is administered weekly for 27 weeks. In some cases, the dose is administered weekly for 28 weeks. In some cases, the dose is administered weekly for 29 weeks. In some cases, the dose is administered weekly for 30 weeks. In some cases, the dose is administered weekly for 31 weeks. In some cases, the dose is administered weekly for 32 weeks. In some cases, the dose is administered weekly for 33 weeks. In some cases, the dose is administered weekly for 34 weeks. In some cases, the dose is administered weekly for 35 weeks. In some cases, the dose is administered weekly for 36 weeks. In some cases, the dose is administered weekly for 37 weeks. In some cases, the dose is administered weekly for 38 weeks. In some cases, the dose is administered weekly for 39 weeks. In some cases, the dose is administered weekly for 40 weeks. In some cases, the dose is administered weekly for 41 weeks. In some cases, the dose is administered weekly for 42 weeks. In some cases, the dose is administered weekly for 43 weeks. In some cases, the dose is administered weekly for 44 weeks. In some cases, the dose is administered weekly for 45 weeks. In some cases, the dose is administered weekly for 46 weeks. In some cases, the dose is administered weekly for 47 weeks. In some cases, the dose is administered weekly for 48 weeks. In some cases, the dose is administered weekly for 49 weeks.In some cases, the dose is administered once weekly for 50 weeks. In some cases, the dose is administered once weekly for 51 weeks. In some cases, the dose is administered once weekly for 52 weeks. In some cases, the dose is administered once weekly for 1 year. In some cases, the dose is administered once weekly for 2 years. In some cases, the dose is administered once weekly for 3 years. In some cases, the dose is administered once weekly for 4 years. In some cases, the dose is administered once weekly for 5 years.

[0128] In some implementations, the dosage is administered weekly at a fixed dose for eight weeks, followed by a four-week titration period. In some cases, the fixed dose is approximately 400 μg to approximately 800 μg. In some cases, the fixed dose is 400 μg. In some cases, the fixed dose is 600 μg. In some cases, the fixed dose is 800 μg. During the four-week titration period, for subjects who cannot discontinue active vitamin D and / or reduce calcium supplementation, an up-titration is performed.

[0129] In some embodiments, this disclosure provides a method of treating a subject suffering from a disease or condition associated with insufficient PTH levels (hypoparathyroidism) or a disease responsive to PTH therapy (such as osteoporosis), the method comprising administering to the subject a dose of at least about 30 μg once weekly, wherein the dose comprises SEQ ID NO: 1. In some cases, the amount of the dose may be as described in other parts of this document. In some cases, a method of treating hypoparathyroidism is provided, wherein a patient requiring such therapy administers compound 1 (SEQ ID NO: 1) in an amount effective in treating or preventing hypoparathyroidism or alleviating a medical condition associated with hypoparathyroidism, as described herein.

[0130] In some implementations, the patients requiring treatment have osteoporosis. In some implementations, the patients requiring treatment have osteoporosis. In some cases, the patients requiring treatment are postmenopausal women. In some cases, the patients requiring treatment have glucocorticoid-induced osteoporosis. In some cases, the patients requiring treatment have glucocorticoid-induced osteoporosis.

[0131] In some embodiments, a method for treating osteoporosis is provided, the method comprising treating a subject in need by weekly subcutaneous injection of compound 1 of the present disclosure (SEQ ID NO: 1).

[0132] In some embodiments, a method for treating kidney injury is provided, the method comprising treating a subject in need by weekly subcutaneous injection of compound 1 of the present disclosure (SEQ ID NO: 1).

[0133] In some embodiments, a method for treating kidney failure is provided, the method comprising treating a subject in need by weekly subcutaneous injection of compound 1 of the present disclosure (SEQ ID NO: 1).

[0134] In another embodiment, this disclosure provides a method for treating osteoporosis, the method comprising treating a subject in need by weekly subcutaneous injection of compound 1 of this disclosure (SEQ ID NO: 1).

[0135] In some implementations, telopeptides of type I collagen can be used as biomarkers for bone resorption. In some cases, bone resorption biomarkers are selected from carboxyl-terminal crosslinkers (CTX-1) and amino-terminal crosslinkers (NTX-1). In some cases, both CTX-1 and NTX-1 are released during collagen degradation. In some cases, CTX-1 can be measured using ELISA with a monoclonal antibody targeting the octapeptide sequence (EKAHD-β-GGR) in the β-isotype α-1(I) chain. In some cases, CTX-1 is a specific and sensitive biomarker for bone resorption, which can rapidly indicate the response of postmenopausal osteoporosis to bisphosphonate therapy. In some cases, serum CTX-1 is affected by food intake, and blood must be drawn in a fasting state because food intake significantly reduces CTX-1 levels.

[0136] In some embodiments, a method for treating a subject with hypoparathyroidism is provided, the method comprising: (a) determining the subject's CTX-1 level after administering SEQ ID NO: 1 to the subject once weekly, and (b) continuing to administer SEQ ID NO: 1 to the subject once weekly, wherein the CTX-1 level is less than about 900 pg / mL. In some cases, the CTX-1 level is less than about 850 pg / mL. In some cases, the CTX-1 level is less than about 800 pg / mL. In some cases, the CTX-1 level is less than about 700 pg / mL. In some cases, the CTX-1 level is less than about 600 pg / mL. In some cases, the CTX-1 level is less than about 500 pg / mL. In some cases, the CTX-1 level is less than about 450 pg / mL. In some cases, the CTX-1 level is less than about 400 pg / mL. In some cases, the CTX-1 level is less than about 300 pg / mL. In some cases, CTX-1 levels are less than about 200 pg / mL. In some cases, CTX-1 levels are higher than about 100 pg / mL. In some cases, CTX-1 levels are higher than about 200 pg / mL. In some cases, CTX-1 levels are higher than about 300 pg / mL. In some cases, CTX-1 levels are higher than about 400 pg / mL. In some cases, CTX-1 levels are higher than about 500 pg / mL. In some cases, CTX-1 levels are higher than about 600 pg / mL. In some cases, CTX-1 levels are higher than about 700 pg / mL. In some cases, CTX-1 levels range from about 50 pg / mL to about 1000 pg / mL. In some cases, CTX-1 levels range from about 50 pg / mL to about 900 pg / mL. In some cases, CTX-1 levels range from about 50 pg / mL to about 800 pg / mL. In some cases, CTX-1 levels are from about 50 pg / mL to about 700 pg / mL. In some cases, CTX-1 levels are from about 50 pg / mL to about 600 pg / mL. In some cases, CTX-1 levels are from about 50 pg / mL to about 500 pg / mL. In some cases, CTX-1 levels are from about 50 pg / mL to about 400 pg / mL. In some cases, CTX-1 levels are from about 50 pg / mL to about 300 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 1000 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 900 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 800 pg / mL.In some cases, CTX-1 levels are from about 200 pg / mL to about 700 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 600 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 500 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 400 pg / mL. In some cases, CTX-1 levels are from about 200 pg / mL to about 300 pg / mL. In some cases, CTX-1 levels are from about 300 pg / mL to about 1000 pg / mL. In some cases, CTX-1 levels are from about 300 pg / mL to about 900 pg / mL. In some cases, CTX-1 levels are from about 300 pg / mL to about 800 pg / mL. In some cases, CTX-1 levels are from about 300 pg / mL to about 700 pg / mL. In some cases, CTX-1 levels are from about 300 pg / mL to about 600 pg / mL. In some cases, CTX-1 levels are from about 300 pg / mL to about 500 pg / mL. In some cases, CTX-1 levels are from about 500 pg / mL to about 1000 pg / mL. In some cases, CTX-1 levels are from about 500 pg / mL to about 900 pg / mL. In some cases, CTX-1 levels are from about 500 pg / mL to about 800 pg / mL. In some cases, CTX-1 levels are from about 500 pg / mL to about 700 pg / mL. In some cases, CTX-1 levels are from about 500 pg / mL to about 600 pg / mL. In some cases, the dose of SEQ ID NO: 1 is once weekly, not exceeding 1000 μg. In some cases, the dose of SEQ ID NO: 1 is as described in other parts of this document (once weekly). In some cases, the assay also includes obtaining a biological sample from the subject and measuring the level of CTX-1 in the sample from the subject. In some cases, the method further includes (c): administering a therapeutically effective amount of an anti-resorptive medication to the subject. In some cases, CTX-1 levels are measured between 1 and 30 days. In some cases, CTX-1 levels are measured between 1 and 15 days. In some cases, CTX-1 levels are measured between 15 and 30 days. In some cases, CTX-1 levels are measured between 12 and 25 days. In some cases, a dose of 200 μg, comprising SEQ ID NO: 1, is administered to the subject prior to measuring the subject's CTX-1 level.In some cases, a dose of 400 μg, containing SEQ ID NO: 1, is administered to the subject before measuring the CTX-1 level. In some cases, a dose of 600 μg, containing SEQ ID NO: 1, is administered to the subject before measuring the CTX-1 level. In some cases, a dose of 900 μg, containing SEQ ID NO: 1, is administered to the subject before measuring the CTX-1 level. In some cases, the CTX-1 level is measured using an ELISA.

[0137] In some embodiments, type I collagen is found in the organic bone matrix (>90%), which develops from type I procollagen in bone. In some cases, type I procollagen is synthesized by fibroblasts and osteoblasts. In some cases, type I procollagen has N-terminal and C-terminal extensions, which are removed by specific proteases during the conversion of procollagen to collagen. In some cases, type I procollagen, including P1CP and P1NP, subsequently conjugates to the bone matrix. In some cases, the bone formation biomarker P1NP is a specific indicator of type I collagen deposition. In some cases, P1NP is released into the intracellular intercellular space during type I collagen formation, and P1NP eventually exists in the bloodstream. In some cases, P1NP is typically released in a trimer structure (derived from the trimer collagen structure) and subsequently rapidly degraded into monomeric forms by thermal degradation. In some cases, the trimer structure of P1NP is detected using an antibody via enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. In some cases, P1NP has been shown to be a more sensitive bone biomarker for measuring bone formation rate in osteoporosis.

[0138] In some embodiments, a method for treating a subject with hypoparathyroidism is provided, the method comprising: (a) determining the level of type I procollagen N-terminal propeptide (P1NP) in the subject after weekly administration of SEQ ID NO: 1, and (b) continuing weekly administration of SEQ ID NO: 1 to the subject, wherein the subject's P1NP level is greater than about -50 μg / L. In some cases, the subject's P1NP level is greater than about -40 μg / L. In some cases, the subject's P1NP level is greater than about -30 μg / L. In some cases, the subject's P1NP level is greater than about -20 μg / L. In some cases, the subject's P1NP level is greater than about -10 μg / L. In some cases, the subject's P1NP level is less than about -30 μg / L. In some cases, the subject's P1NP level is less than about -20 μg / L. In some cases, the subject's P1NP level is less than about -10 μg / L. In some cases, the subject's P1NP level is less than about -5 μg / L. In some cases, P1NP levels ranged from approximately -5 μg / L to -50 μg / L. In some cases, P1NP levels ranged from approximately -5 μg / L to -40 μg / L. In some cases, P1NP levels ranged from approximately -5 μg / L to -30 μg / L. In some cases, P1NP levels ranged from approximately -5 μg / L to -20 μg / L. In some cases, P1NP levels ranged from approximately -5 μg / L to -10 μg / L. In some cases, P1NP levels ranged from approximately -10 μg / L to -50 μg / L. In some cases, P1NP levels ranged from approximately -10 μg / L to -40 μg / L. In some cases, P1NP levels ranged from approximately -10 μg / L to -30 μg / L. In some cases, P1NP levels ranged from approximately -10 μg / L to -20 μg / L. In some cases, P1NP levels were approximately -20 μg / L to -50 μg / L. In some cases, P1NP levels were approximately -20 μg / L to -40 μg / L. In some cases, P1NP levels were approximately -20 μg / L to -30 μg / L. In some cases, P1NP levels were measured between 1 and 30 days. In some cases, P1NP levels were measured between 1 and 15 days. In some cases, P1NP levels were measured between 15 and 30 days. In some cases, P1NP levels were measured between 12 and 25 days. In some cases, a dose of 200 μg, containing SEQ ID NO: 1, was administered to the subject before determining the P1NP level. In some cases, a dose of 400 μg, containing SEQ ID NO: 1, was administered to the subject before determining the P1NP level.In some cases, a dose of 600 μg, containing SEQ ID NO: 1, is administered to the subject before determining the P1NP level. In some cases, a dose of 900 μg, containing SEQ ID NO: 1, is administered to the subject before determining the P1NP level. In some cases, the P1NP level is measured using an Elecsys 2010 automated analyzer.

[0139] In some implementations, any of the methods described herein results in an increase in the subject's serum calcium level. In some cases, this is achieved through a maximum increase in serum calcium (E0). max,adj Serum calcium is assessed using total serum calcium levels (AUEC0-τ, adj) between injections. In some cases, the maximum increase in albumin-adjusted serum calcium is observed approximately 48 hours after injection. In some cases, the increase in serum calcium is almost maximum after the third weekly injection.

[0140] The compounds described herein can be used to prepare medicaments for the prevention or treatment of diseases or conditions. Furthermore, methods for treating any of the diseases or conditions described herein in a subject requiring such treatment involve administering to the subject, in a therapeutically effective amount, a pharmaceutical composition containing at least one compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0141] The compounds described herein can be applied for preventative and / or therapeutic treatment. In therapeutic use, the composition is applied to a subject suffering from the disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. The effective amount for this purpose will depend on the severity and course of the disease or condition, prior treatment, the subject's health status, weight, and response to the drug, as well as the judgment of the treating physician.

[0142] In some embodiments, the compounds of this disclosure (e.g., compound 1) may be administered alone or in combination with other agents, such as bone resorption inhibitors including calcitonin, bisphosphonates, SERMs (e.g., raloxifene), hormone replacement therapy (HRT), calcium, vitamin D1, vitamin D2, vitamin D3, vitamin D4, and estrogen. The compounds of this disclosure may be administered co-administered with another agent. Alternatively, the compounds of this disclosure may be administered sequentially with another agent; for example, the compounds of this disclosure may be administered alone for a period of one week to one year, followed by administration of another agent, which may be administered together with the compound, or in the absence of the compound.

[0143] In prophylactic applications, compositions containing the compounds described herein are administered to subjects who are susceptible or otherwise at risk of developing a particular disease, condition, or illness. Such a quantity is defined as a “preventative effective amount or dose.” In this application, the precise amount also depends on the subject’s health condition, weight, etc. When used on a subject, the effective amount for this purpose will depend on the severity and duration of the disease, condition, or illness, prior treatments, the subject’s health condition and response to the medication, and the judgment of the treating physician.

[0144] In cases where the patient’s condition does not improve, the compound may be administered for an extended period of time, including throughout the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, as determined by the physician.

[0145] Once the subject's condition improves, a maintenance dose may be administered if necessary. Subsequently, the dose or frequency of administration may be reduced, or both, depending on symptoms, until the improved level of disease, symptom, or condition is maintained. However, the subject may require long-term intermittent treatment should any symptoms recur.

[0146] The amount of the given agent corresponding to this quantity will vary depending on factors such as the specific compound, the disease or condition and its severity, and the characteristics of the subject or host requiring treatment (e.g., weight), but can still be determined in a manner recognized in the art based on the specific circumstances surrounding the case (including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated). However, in general, the dose for adult treatment is typically in the range of about 0.02 to about 5000 mg per day, and in some embodiments, about 1 to about 1500 mg per day. The required dose can be conveniently presented as a single dose or as multiple doses administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four, or more sub-dose times per day.

[0147] The pharmaceutical compositions described herein may be presented in unit dosage forms suitable for single, precise dose administration. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose may be in the form of a package containing discrete amounts of the formulation. Non-limiting examples include packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-resealable containers. Alternatively, multi-dose, resealable containers may be used, in which case preservatives are typically included in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage forms, including but not limited to ampoules, or in multi-dose containers (with added preservatives).

[0148] The toxicity and efficacy of such treatment regimens can be determined through standard pharmaceutical procedures in cell culture or laboratory animals, including but not limited to determining LD50. 50 (The dose that makes 50% of the population lethal) and ED 50 (The dose effective for 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as LD50. 50 With ED 50 The ratio between these values. Compounds exhibiting a high therapeutic index are preferred. Data from cell culture assays and animal studies can be used to determine dosage ranges for human use. The dosage of such compounds is preferably within the range of ED. 50 And within the range of cyclic concentrations with the lowest toxicity. Dosage can vary within this range depending on the dosage form and route of administration.

[0149] In some embodiments, the present invention provides a method for treating or preventing a disease, state, or condition in a subject of need, the method comprising administering to the subject an effective amount of a compound of any embodiment of the present invention or a pharmaceutically acceptable salt thereof. The disease, state, or condition may be selected from the group described elsewhere herein.

[0150] The following examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0151] Example The following synthetic schemes are provided for illustrative purposes and not for limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to them. It should also be understood that those skilled in the art will be able to prepare them in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as needed. Generally, starting materials and reagents can be obtained from commercial suppliers, synthesized from sources known to those skilled in the art, or prepared as described herein.

[0152] Example 1: Synthesis Procedure Compound 1 (SEQ ID NO: 1) was synthesized using a similar synthetic procedure as shown in WO2021242756A2 (PCT / US2021 / 034055) and US20230285578A1.

[0153] Table 1: Compounds with SEQ ID NO Example 2: Phase 1, randomized, double-blind, placebo-controlled safety, tolerability, pharmacokinetic and pharmacodynamic studies of compound 1 in healthy participants with single and multiple escalation doses.

[0154] Compound 1 (SEQ ID NO: 1) was investigated as a potential treatment for hypoparathyroidism. Compound 1 was administered subcutaneously.

[0155] patient: Adults aged 21 to 60.

[0156] standard: Inclusion criteria: • Healthy men and women aged 20 to 60 (inclusive) with no reproductive potential.

[0157] • Body mass index between 20.0 and 32.0 kg / m2 (inclusive).

[0158] • No clinically significant results were found during physical examination, electrocardiogram, laboratory tests, or vital signs.

[0159] • The recipient has signed an informed consent form.

[0160] Exclusion criteria: • Any history of serious illness or condition.

[0161] • Acute illness within 30 days of the first dose of the investigational drug.

[0162] • Positive screening results for HIV, hepatitis B, or hepatitis C.

[0163] • Have a history of substance abuse (drugs or alcohol) within the past year or currently abuse substances, or have tested positive for substance abuse during screening.

[0164] • Use of nicotine-containing products or e-cigarettes within 3 months prior to screening or registration. • Use of cannabis within 45 days prior to registration.

[0165] • Donate blood within 3 months before screening, plasma within 2 weeks before screening, or platelets within 6 weeks before screening.

[0166] • Participated in any other investigational drug trial that has been accepted for investigational drug status within the past 30 days.

[0167] Research Design: • This trial was designed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of compound 1 versus placebo in healthy participants. Figure 1 ).

[0168] Main objectives: • Evaluate the safety and tolerability of compound 1 versus placebo in healthy participants.

[0169] Secondary objectives: • Evaluate the pharmacokinetic and pharmacodynamic effects of compound 1 versus placebo in healthy participants.

[0170] Adverse events: Compound 1 was well tolerated for more than four weeks at different test doses (Table 2). No serious adverse events or treatment-induced adverse events (TEAEs) occurred. Asymptomatic hypercalcemia was observed. Adverse events leading to discontinuation of the study drug were: 4 cases of COVID-19 and 2 cases of hypercalcemia. The only TEAE occurring in ≥3 participants (any cohort) was COVID-19.

[0171] Table 2: a The most common TEAEs are defined as those that occur in ≥3 patients in any treatment group.

[0172] Example 3: PK Evaluation Compound 1 was administered subcutaneously to subjects at different doses, and blood samples were collected to perform pharmacokinetic (PK) assessments. PK assessments were calculated using standard methods. PK data are presented in [the table / document / etc.]. Figure 2 And as shown in Table 3 below. Compounds 1 and 2 showed linear and dose-proportional plasma concentrations.

[0173] The peak-to-valley ratio is calculated using the ratio between the highest and lowest plasma concentrations of compound 2 at steady state. For example... Figure 2 As shown, the highest and lowest plasma concentrations resulted in a peak-to-trough ratio of approximately 1.47 to 1.79 for the active drug.

[0174] The half-lives of compounds 1 and 2 were calculated using standard methods and are shown in Table 3. Furthermore, Figure 2 The results showed that repeated administration of compound 1 led to the accumulation of the active drug (compound 2) until a steady state was reached.

[0175] Table 3 PD assessment: Compound 1 was administered subcutaneously to subjects at different doses, and blood samples were collected to perform pharmacodynamic (PD) assessments. C-terminal telopeptide (CTX) biomarkers were measured and presented. Figure 3In this study, the biomarker of type I procollagen N-terminal propeptide (P1NP) was measured and presented. Figure 4 middle.

[0176] PD assessment also includes evaluating changes in albumin-adjusted serum calcium levels and suppression of endogenous PTH secreted by the parathyroid glands. Figure 7 Serum calcium levels are measured by the maximum increase in serum calcium (E). max,adj ()( Figure 6A ) or total serum calcium level between injections (AUEC0-τ, adj)( Figure 6B The assessment was conducted in a dose-dependent and time-dependent manner.

[0177] Example 4: A phase II, randomized, double-blind, placebo-controlled study of compound 1 in adult patients with hypoparathyroidism.

[0178] The safety, tolerability, and efficacy of three doses of compound 1 (SEQ ID NO: 1) were investigated over a 12-week period. The primary endpoint of the Phase 2 clinical trial was the proportion of patients who, after 12 weeks of treatment, could discontinue active vitamin D and reduce calcium supplementation to less than or equal to 1000 mg daily while maintaining normal serum calcium levels. Secondary endpoints included the safety and tolerability of compound 1, characterization of pharmacokinetic and pharmacodynamic activities (including urinary calcium, serum phosphorus, 1,25-dihydroxyvitamin D, and bone biomarkers), and assessment of the impact on quality of life using patient-reported outcome tools. The primary objective of the Phase 2 clinical trial was to define an effective, safe, and well-tolerated dose of compound 1 that allowed for the orderly discontinuation of active vitamin D and calcium supplementation while maintaining normal serum and urinary calcium levels.

[0179] Patients were randomized (1:1:1:1) to receive weekly subcutaneous injections of placebo and 400 µg, 600 µg, and 800 µg of compound 1. The 12-week treatment period consisted of an eight-week fixed-dose period and a four-week titration period. During the titration period, patients who were unable to discontinue active vitamin D and / or reduce calcium supplementation could have their titer of the study drug increased using the protocol-specified algorithm. Patients who completed the 12-week treatment period were eligible to participate in the 104-week long-term extension study.

Claims

1. A pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the release half-life of SEQ ID NO: 2 is greater than about 100 hours.

2. The pharmaceutical composition according to claim 1, wherein the release half-life is greater than about 130 hours.

3. The pharmaceutical composition according to claim 1 or 2, wherein the release half-life is greater than about 140 hours.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the release half-life is less than 250 hours.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the release half-life is less than 200 hours.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein SEQ ID NO: 2 is generated by autocleavage of SEQ ID NO: 1 in vivo.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

8. The pharmaceutical composition according to any one of claims 1 to 7, for treating hypoparathyroidism in a subject of need.

9. The pharmaceutical composition according to any one of claims 1 to 7, for treating osteoporosis or osteopenia in a subject of need.

10. A method for treating hypoparathyroidism, the method comprising administering to a subject in need the pharmaceutical composition of any one of claims 1 to 7.

11. A method for treating osteoporosis or osteopenia, the method comprising administering to a subject in need the pharmaceutical composition of any one of claims 1 to 7.

12. A method of treating a subject suffering from hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject once weekly a dose of at least about 30 μg, wherein the dose comprises the pharmaceutical composition of any one of claims 1 to 7.

13. A method of treating a subject suffering from hypoparathyroidism, osteoporosis, or osteopenia, the method comprising administering to the subject once weekly a dose of at least about 30 μg, wherein the dose comprises SEQ ID NO:

1.

14. The method of claim 13, wherein the dose is at least about 50 μg.

15. The method according to claim 13 or 14, wherein the dose is at least about 200 μg.

16. The method according to any one of claims 13 to 15, wherein the dose is at least about 400 μg.

17. The method according to any one of claims 13 to 16, wherein the dose is up to about 1000 μg.

18. The method according to any one of claims 13 to 17, wherein the dose is up to about 900 μg.

19. The method according to any one of claims 13 to 18, wherein the dose is up to about 600 μg.

20. The method of claim 13, wherein the dose is about 50 μg, about 150 μg, about 200 μg, about 300 μg, about 400 μg, about 460 μg, about 600 μg, or about 900 μg.

21. The method of claim 13, wherein the dose is about 50 μg.

22. The method of claim 13, wherein the dose is about 150 μg.

23. The method of claim 13, wherein the dose is about 200 μg.

24. The method of claim 13, wherein the dose is about 300 μg.

25. The method of claim 13, wherein the dose is about 400 μg.

26. The method of claim 13, wherein the dose is about 460 μg.

27. The method of claim 13, wherein the dose is about 600 μg.

28. The method of claim 13, wherein the dose is about 900 μg.

29. The method according to any one of claims 13 to 28, wherein the method is used to treat hypoparathyroidism in a subject of need.

30. The method according to any one of claims 13 to 28, wherein the method is used to treat osteoporosis or osteopenia in a subject of need.

31. A pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the pharmacokinetic profile of SEQ ID NO: 2 after administration of SEQ ID NO: 1 exhibits a peak-to-trough ratio of less than about 2 in plasma.

32. The pharmaceutical composition of claim 31, wherein the peak-to-trough ratio in plasma is less than about 1.

8.

33. The pharmaceutical composition according to claim 31 or 32, wherein the peak-to-trough ratio in plasma is less than about 1.

6.

34. The pharmaceutical composition according to any one of claims 31 to 33, wherein the peak-to-trough ratio in plasma is greater than about 1.

1.

35. The pharmaceutical composition according to any one of claims 31 to 34, wherein the peak-to-trough ratio in plasma is greater than about 1.

2.

36. The pharmaceutical composition according to any one of claims 31 to 35, wherein the peak-to-trough ratio in plasma is about 1.

4.

37. The pharmaceutical composition according to any one of claims 31 to 35, wherein the peak-to-trough ratio in plasma is about 1.

5.

38. The pharmaceutical composition according to any one of claims 31 to 37, wherein the peak-to-trough ratio is measured under steady state after subcutaneous administration of the pharmaceutical composition.

39. The pharmaceutical composition according to any one of claims 31 to 38, wherein the peak-to-trough ratio is measured about 250 hours after subcutaneous administration of the pharmaceutical composition.

40. The pharmaceutical composition according to any one of claims 31 to 39, wherein the peak-to-trough ratio is measured about 200 hours after subcutaneous administration of the pharmaceutical composition.

41. The pharmaceutical composition according to any one of claims 31 to 40, wherein the peak-to-trough ratio is measured about 48 hours after subcutaneous administration of the pharmaceutical composition.

42. The pharmaceutical composition according to any one of claims 31 to 41, wherein the subcutaneous administration is performed by subcutaneous injection.

43. The pharmaceutical composition according to any one of claims 31 to 42, wherein the subcutaneous administration is performed using a pen-type device.

44. The pharmaceutical composition according to any one of claims 31 to 43, wherein the subject of administration is a human.

45. The pharmaceutical composition according to any one of claims 31 to 44, wherein the subject of administration is a monkey.

46. ​​A method for treating a subject suffering from hypoparathyroidism, the method comprising: (a) After administering SEQ ID NO: 1 to the subjects once a week, the levels of CTX-1 in the subjects were measured, and (b) Continue to administer SEQ ID NO: 1 to the subject once a week, wherein the level of CTX-1 is less than 900 pg / mL.

47. The method of claim 46, wherein the level of CTX-1 is less than 400 pg / mL.

48. The method of claim 46 or 47, wherein the dose comprising SEQ ID NO: 1 is administered to the subject, wherein the dose is less than 1000 μg once a week.

49. The method according to any one of claims 46 to 48, wherein the determination further comprises obtaining a biological sample from the object and measuring the level of CTX-1 in the sample from the object.

50. The method according to any one of claims 46 to 49, further comprising (c): administering a therapeutically effective amount of the anti-absorption drug to the subject.

51. A method for treating a subject suffering from hypoparathyroidism, the method comprising: (a) After weekly administration of SEQ ID NO: 1 to the subjects, the levels of type I procollagen N-terminal propeptide (P1NP) in the subjects were determined, and (b) Continue to administer SEQ ID NO: 1 to the subject once a week, wherein the level of P1NP in the subject is greater than about -50 μg / L.

52. The method of claim 51, wherein the dose comprising SEQ ID NO: 1 is administered to the subject, wherein the dose is less than 1000 μg once a week.

53. The method of claim 51 or 52, wherein the determination further comprises obtaining a biological sample from the object and measuring the level of P1NP in the sample from the object.

54. The method of claim 53, further comprising (c): administering a therapeutically effective amount of the anti-absorption drug to the subject.

55. A pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein when the dose comprising SEQ ID NO: 1 is administered to a subject, the maximum plasma concentration (C2) of SEQ ID NO: 2 is achieved. max The concentration is up to about 6 (nmol / L), where the dose is between 200 μg and 900 μg.

56. The pharmaceutical composition of claim 55, wherein the dose is administered once weekly.

57. The pharmaceutical composition according to claim 55 or 56, wherein the maximum plasma concentration (C) of SEQ ID NO: 2 is [missing information]. max The concentration is at most about 5 (nmol / L).

58. The pharmaceutical composition according to any one of claims 55 to 57, wherein the maximum plasma concentration (C) of SEQ ID NO: 2 is... max The value is at least about 0.8 (nmol / L).

59. The pharmaceutical composition according to any one of claims 55 to 58, wherein the maximum plasma concentration (C) of SEQ ID NO: 1 is... max The concentration is at most about 20 (nmol / L).

60. The pharmaceutical composition according to any one of claims 55 to 59, wherein the maximum plasma concentration (C) of SEQ ID NO: 1 is [missing information]. max The concentration is at least about 3 (nmol / L).

61. The pharmaceutical composition according to any one of claims 55 to 60, wherein the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 3 to about 7.

62. The pharmaceutical composition according to any one of claims 55 to 61, wherein the Cmax ratio of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4 to about 6.

63. A pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once weekly, wherein the half-life of SEQ ID NO: 2 is greater than about 100 hours.

64. The pharmaceutical composition of claim 63, wherein the half-life is greater than about 130 hours.

65. The pharmaceutical composition according to claim 63 or 64, wherein the release half-life is greater than about 140 hours.

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