Pharmaceutical compositions and uses thereof

Abstract

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

Description

PHARMACEUTICAL COMPOSITIONS AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Applications Nos. 63 / 590,345 filed on October 13, 2023; and 63 / 638,538 filed on April 25, 2024; the entire contents of each of which are incorporated herein by reference. BACKGROUND

[0002] Through secretion of parathyroid hormone (PTH), the parathyroid gland controls calcium in the blood in a very tight range (8-10 mg / dL in adults). Calcium, which is stored in bones, is released in response to PTH, supporting central nervous system functioning, blood vessel and muscle contraction, enzyme and hormone secretion, and blood clotting. Mechanistically, PTH increases concentrations of calcium by stimulating the production of biologically-active forms of vitamin D within the kidney, while mobilizing calcium and phosphate to be released from the bones, signaling kidneys to eliminate excess phosphate, and maximizing tubular reabsorption of calcium within the kidneys.

[0003] Hypoparathyroidism (hypo PT) is an uncommon disease in which there is insufficient production of PTH. Subjects with hypo PT excrete too much calcium in their urine, have too much phosphate in their blood, and have abnormally low bone turnover. Until the approval of NPS / Shire’s Natpara® (rhPTH) by the Food and Drug Administration (FDA) in January of 2015, hypoparathyroidism was one of the very few classic endocrine diseases not treated by hormone replacement. Natpara® provides only modest efficacy relative to the standard of care consisting of high dose calcium and vitamin D supplements. Even so, the drug has been well received since its 2015 commercial launch, demonstrating the significant unmet need that exists in treating hypo PT.

[0004] Because hypo PT is a rare disease, drugs being developed for hypo PT benefit from the Orphan Drug Designations from the FDA and European Medicines Agency (EMA). Each emerging competitor is directed at restoration of PTH in a more physiologic manner than Natpara®, to primarily normalize serum calcium and diminish long-term consequences of disease insufficiently managed. The competitors differ in their approach to normalizing PTH, with sizable differences in product profile, that include routes of administration, potency, dose frequency and therapeutic index. The compositions disclosed herein provide a weekly treatment for subjects with hypo PT that will restore and maintain physiologic levels of PTH safely throughout the week, offering unique pharmacological benefit and significant convenience for subjects.

[0005] Hypo PT can be divided into primary and secondary disease. Primary disease occurs when there are intrinsic defects within the parathyroid glands, from genetic causes. Hypo PT from genetic causes is especially rare, thought to cause less than 10% of total cases. Secondary, or acquired, disease occurs when a previously functioning parathyroid gland function is impaired, destroyed or ablated. Secondary disease is by far the most common, causing approximately 90% of total cases.

[0006] At least 75% of acquired hypo PT cases are caused by anterior neck surgery (i.e., total thyroidectomy or radical neck dissection for head and neck malignancies), due to inadvertent or unavoidable removal of or damage to parathyroid glands and / or their blood supply. Transient hypo PT after thyroid surgery is relatively common, occurring in an estimated 7-46% of thyroid surgeries. Transient hypo PT resolves within weeks or months of surgery. Chronic hypo PT is rare, occurring at a rate of 0.9-1.6% in surgical centers with experienced endocrine surgeons and a high case volume. However, rates as high as 6.6% have been reported post thyroid surgery, emphasizing the importance of expertise and experience in avoiding permanent damage resulting in hypo PT.

[0007] After anterior neck surgery, the next most common acquired cause of hypo PT in adults is thought to be autoimmune disease. It can affect either the parathyroid glands alone or multiple endocrine glands. Autoimmune mediated disease is estimated to cause less than 10% of acquired hypo PT. Other secondary causes include rare infiltrative disorders due to metastatic disease or iron / copper overload, ionizing radiation exposure, or can be of unknown origin (idiopathic).

[0008] Estimates of hypo PT prevalence in the US range from 60,000 to 115,000 patients. Experts suggest the best estimate, which is based on a large health plan claims database, is 77,000 patients, of which 58,793 were insured. Data for other regions are extremely limited, and documented estimates range from 70,000 to 267,000 for Europe, 20,000 for Japan, and 30,000 for the rest of the world.

[0009] Chronic hypo PT is a growing disease, driven by incidence of thyroid disease, including cancer, and its treatments, most notably surgery. For example, between 1996 and 2006, the total number of thyroidectomies performed in the US increased 39%, from 66,864 to 92,931. It is estimated that the number of thyroidectomies performed in the US each year has now reached 150,000. The number of people potentially affected by hypo PT is growing. Because thyroid disease impacts women more than men, more than 70% of patients with hypo PT are women.

[0010] Most people with calcium levels residing outside normal physiological range feel sick. Because of calcium’s crucial role in nerve and muscle function, patients with hypocalcemia may experience tingling or burning in extremities (paresthesia), muscle twitching, muscle pain, involuntary muscle contractions (tetany), dry / rough skin, inability to concentrate or focus, anxiety and / or depression. Severely low levels of blood calcium can cause life-threatening laryngospasm, seizures, or cardiac arrhythmias, requiring emergency treatment with IV calcium. Serious long- term consequences of hypo PT can include nephrocalcinosis, impaired renal function / chronic kidney disease, calcium deposits in soft tissues, and overly mineralized bones.

[0011] Hypo PT is typically diagnosed through clinical history and laboratory tests. The diagnosis is typically characterized by low / undetectable levels of serum PTH and hypocalcemia, defined as total serum calcium below the lower limit of normal, and hyperphosphatemia. Levels of activated vitamin D and bone turnover markers are also typically in the lower portion of normal to overtly low range, and excretion of calcium is increased. Such lab results in the context of a recent neck surgery can result in a straightforward diagnosis of hypo PT. However, cases of hypo PT can be very difficult to diagnose, especially when there is no known damage to the parathyroid gland.

[0012] There are no definitive guidelines for the treatment of hypo PT, so treatment is based upon experience and clinical judgment. Generally accepted primary goals of chronic treatment are to maintain within an acceptable range serum total calcium (low to low-normal range), serum phosphorus (high-normal range), 24-hour urine calcium excretion (<7.5 mmol / d) and calcium phosphate product (under 4.4 mmol2 / L2).

[0013] Standard treatment includes calcium, vitamin D metabolites, and sometimes thiazide diuretics. Recommended calcium supplements are calcium carbonate and calcium citrate, and the amount needed varies greatly (9-fold) among patients. 1,25(OH)2D3 (calcitriol) is an active metabolite of vitamin D and helps maintain serum calcium by improving the efficiency of intestinal calcium absorption. Calcitriol is also administered over a wide (8-fold) dosing range. By enhancing distal renal tubular calcium reabsorption, thiazide diuretics (drugs in the benzothiadiazines class) can also be useful in treating hypo PT.

[0014] While it may sound straightforward to replenish deficient calcium with calcium and vitamin D supplements, the reality is that it is extremely difficult to achieve good control. Most patients experience a roller coaster in dosing levels that alternate between too high and too low. Also, calcium and vitamin D supplements do nothing to restore the underlying PTH deficiency, which has therapeutic consequence.

[0015] Patients with hypo PT experience a heavy burden of illness, with significant, negative impact to their daily quality of life, and to the lives of their caregivers, families, and friends. NPS Pharmaceuticals conducted a 374-patient epidemiology study, PARADOX, to assess clinical, social, and economic implications of hypo PT. Data were collected through a 30-minute, web- based instrument which was developed with input from clinical experts, the Hypoparathyroidism Association, and patients. This instrument was primarily disseminated via email to Hypoparathyroidism Association members, including adults in the US who had been living with hypo PT for six or more months. Results were published by Hadker et al in Endocrine Practice, with the following key highlights: (i) 72% experienced more than 10 symptoms daily, with the most frequently reported: (ii) Physical symptoms: fatigue (82%), muscle pain / cramping (78%), paresthesia (76%), tetany (70%), joint or bone pain (67%), and pain or weakness in the extremities (53%) (iii)Emotional symptoms: anxiety (59%) and depression (53%) (iv)Cognitive symptoms: brain fog / mental lethargy (72%), inability to concentrate (65%), memory loss (61.5%) and sleep disturbances (57%) (v) 79% required hospital stays or emergency department visits (vi) 45% reported significant interference with their lives (vii) 85% reported an inability to perform household activities, and (viii) 20% experienced a disease-associated (negative) change in employment status.

[0016] Other publications have also confirmed the illness burden of hypo PT. A cross-sectional study published by Arlt et al in the European Journal of Endocrinology compared well-being and mood, using validated questionnaires in 25 women with postsurgical hypo PT who were stably managed with treatment of calcium and vitamin D to 25 women with intact parathyroid function following thyroid surgery. Hypo PT patients had significantly higher global complaint scores in the Geissen complaint list, the von Zerssen symptom list, and Symptom Checklist-90, with increases in subscale scores for anxiety, phobic anxiety, and their physical equivalents. Importantly, the current conventional standard of therapy for hypo PT treatment did not restore well-being in these patients. SUMMARY OF THE INVENTION

[0017] It is often desirable to extend the release time of an injected drug to increase its duration of action, or to reduce its toxic effects. Formulations that are readily soluble in the body are usually absorbed rapidly and provide a sudden burst of available drug as opposed to a more desirable and gradual release of the pharmacologically active product.

[0018] A variety of attempts have been made to provide controlled and extended-release pharmaceutical compounds, but previously disclosed techniques have not succeeded in overcoming all of the problems associated with the technology, such as achieving an optimal extended-release time, maximizing stability and efficacy, reducing toxicity, maximizing reproducibility in preparation, and eliminating unwanted physical, biochemical, or toxicological effects introduced by undesirable matrix materials. Accordingly, there is a need for formulations that safely and efficaciously extend the half-life of existing pharmaceuticals and improve their therapeutic index from dose to dose and from patient to patient. This is of utmost importance in drugs that have a narrow therapeutic index to separate the dose for efficacy from that of toxicity. PTH much like insulin or thyroid hormone is recognized as such a drug where slightly excessive elevation in calcium beyond the physiological range has acute and chronic adverse consequences.

[0019] Mechanisms for providing extended release and an enhanced therapeutic index include sequestering molecules at the injection site or the use of prodrug derivative forms of the pharmaceutical, wherein the prodrug derivative is designed to delay onset of action and extend the half-life of the drug. The delayed onset of action is advantageous in that it allows systemic distribution of the prodrug prior to its activation. Accordingly, the administration of prodrugs can eliminate complications caused by peak activities upon administration and increase the therapeutic index of the parent drug.

[0020] Furthermore, receptor recognition and subsequent processing of peptide and protein agonists is the primary route of degradation of many peptide and protein-based drugs. Thus, binding of the peptide drug to its receptor will result in biological stimulation but will also initiate the subsequent deactivation of the peptide / protein induced pharmacology through the enzymatic degradation of the peptide or protein. Therefore, the use of prodrugs can also delay the time of action for administered drugs to allow an even distribution throughout the body prior to activation. The present disclosure provides compositions and methods to safely extend the biological action of PTH while minimizing excessive action shortly after administration.

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

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

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

[0024] In another aspect, the present disclosure provides a method of treating a subject with hypoparathyroidism, comprising: (a) determining a level of C-terminal telopeptide (CTX) of the subject upon once a week administration of SEQ ID NO: 1 to the subject, and (b) providing continued once a week administration of SEQ ID NO: 1 to the subject, wherein the level of CTX is less than 900 pg / mL.

[0025] In another aspect, the present disclosure provides a method of treating a subject with hypoparathyroidism, comprising: (a) determining a level of Procollagen type I N-terminal propeptide (P1NP) of the subject upon weekly administration of SEQ ID NO: 1 to the subject, and (b) providing continued once a week administration of SEQ ID NO: 1 to the subject, wherein the level of P1NP is greater than about -50 μg / L in the subject. INCORPORATION BY REFERENCE

[0026] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0028] FIG.1 illustrates the Phase 1 study design, objectives, and end points.

[0029] FIG. 2 illustrates the plasma concentration of compound 1 and 2 following weekly administration of compound 1 at various doses.

[0030] FIG. 3 illustrates the mean change from baseline in CTX marker following weekly administration of compound 1 at various doses.

[0031] FIG. 4 illustrates the mean change from baseline in P1NP marker following weekly administration of compound 1 at various doses.

[0032] FIG.5 illustrates the possible mechanism of action of compound 1 and its conversion to compound 2.

[0033] FIG. 6A illustrates maximum serum calcium levels (Emax,adj) following weekly administration of compound 1 at various doses and time points.

[0034] FIG. 6B illustrates total serum calcium levels (AUEC0-τ, adj) following weekly administration of compound 1 at various doses and time points.

[0035] FIG.7. Illustrations endogenous PTH in healthy patients following weekly administration of compound 1 at various doses and time points. DETAILED DESCRIPTION OF THE INVENTION

[0036] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0037] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0039] As used herein an “effective” amount or a “therapeutically effective amount” of a drug refers to a nontoxic amount but enough of the drug to provide the desired effect. The amount that is effective will vary from subject to subject or even within a subject overtime, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify an exact effective amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0040] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0041] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with 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, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0042] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0043] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0044] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which 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) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0045] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0046] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0047] As used herein the term "peak to trough ratio" refers to the ratio between the highest plasma concentration and the lowest plasma concentration of a compound (e.g., compound 2) at steady state.

[0048] As used herein, the term “phosphate buffered saline” or “PBS” refers to aqueous solution comprising sodium chloride and sodium phosphate. Different formulations of PBS are known to those skilled in the art but for purposes of this disclosure the phrase “standard PBS” refers to a solution having have a final concentration of 137 mM NaCl, 10 mM Phosphate, 2.7 mM KCl, and a pH of 7.2-7.4.

[0049] As used herein the terms “native” or “natural” define a condition found in nature. A “native amino acid” is an amino acid present in nature that was produced by natural means.

[0050] As used herein the term “amino acid” encompasses any molecule containing both amino and carboxyl functional groups, wherein the amino and carboxylate groups are attached to the same carbon (the alpha carbon). The alpha carbon optionally may have one or two further organic substituents. An amino acid can be designated by its three-letter code, one letter code, or in some cases by the name of its side chain. For example, a non-canonical amino acid comprising a cyclohexane group attached to the alpha carbon is termed “cyclohexane” or “cyclohexyl.” For the purposes of the present disclosure designation of an amino acid without specifying its stereochemistry is intended to encompass either the L or D form of the amino acid, or a racemic mixture. However, in the instance where an amino acid is designated by its three-letter code (e.g., Lys) or single letter (e.g., K), such a designation is intended to specify the native L form of the amino acid, whereas the D form will be specified by inclusion of a lower-case d before the three- letter code or single code (i.e., dLys or dK). As used herein the designation of a specific amino acid is intended to encompass the native amino acid as well as any isotopically enriched derivative thereof that differs in molecular weight from the native amino acid but has equivalent physical and biological properties as the native amino acid.

[0051] As used herein the term “hydroxyl acid” refers to amino acids that have been modified to replace the alpha carbon amino group with a hydroxyl group.

[0052] As used herein the term “non-coded (non-canonical) 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, Tyr.

[0053] A “dipeptide” is the result of the linkage of an alpha amino acid or an alpha hydroxyl acid to another amino acid, through a peptide bond.

[0054] As used herein the term “chemical cleavage” absent any further designation encompasses a non-enzymatic reaction that results in the breakage of a covalent chemical bond.

[0055] As used herein an “acylated” amino acid is an amino acid comprising an acyl group which is non-native to a naturally occurring amino acid, regardless of the means by which it is produced. Exemplary methods of producing acylated amino acids and acylated peptides are known in the art and include acylating an amino acid before inclusion in the peptide or peptide synthesis followed by chemical acylation of the peptide. In some embodiments, the acyl group causes the peptide to have one or more of (i) a prolonged half-life in circulation, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) an improved resistance to proteases, such as DPP-IV, and (v) altered potency at a receptor for PTH.

[0056] A “bioactive peptide” refers to peptides which can exert a biological effect in vitro and / or in vivo. As used herein a general reference to a peptide is intended to encompass peptides that have modified amino and carboxy termini. For example, an amino acid sequence designating the standard amino acids is intended to encompass standard amino acids at the N- and C- terminus as well as a corresponding hydroxyl acid at the N-terminus and / or a corresponding C-terminal amino acid modified to comprise an amide group in place of the terminal carboxylic acid.

[0057] As used herein an “acylated” amino acid is an amino acid comprising an acyl group which is non-native to a naturally occurring amino acid, regardless of the means by which it is produced. Exemplary methods of producing acylated amino acids and acylated peptides are known in the art and include acylating an amino acid before inclusion in the peptide or peptide synthesis followed by chemical acylation of the peptide. In some embodiments, the acyl group causes the peptide to have one or more of (i) a prolonged half-life in circulation, (ii) a delayed onset of action, (iii) an extended duration of action, (iv) an improved resistance to proteases, such as DPP-IV, and (v) altered potency at a receptor for PTH.

[0058] As used herein, an “alkylated” amino acid is an amino acid comprising an alkyl group which is non-native to a naturally occurring amino acid, regardless of the means by which it is produced. Exemplary methods of producing alkylated amino acids and alkylated peptides are known in the art and including alkylating an amino acid before inclusion in the peptide or peptide synthesis followed by chemical alkylation of the peptide.

[0059] As used herein a “receptor” is a molecule that recognizes and binds with specific molecules in a high affinity interaction, producing some biological effect (either directly or indirectly) in a cell, or on the cells and / or tissues of the host organism. A “cellular receptor” is a molecule on or within a cell that recognizes and binds with specific molecules, producing some effect (either directly or indirectly) in the cell.

[0060] The term “identity” as used herein relates to the similarity between two or more sequences. Identity is measured by dividing the number of identical amino acid residues by the total number of residues and multiplying the product by 100 to achieve a percentage. Thus, two copies of exactly the same sequence have 100% identity, whereas two sequences that have 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 that employ algorithms such as BLAST (Basic Local Alignment Search Tool, Altschul et al. (1993) J. Mol. Biol.215:403-410) are available for determining sequence identity.

[0061] As used herein an amino acid “substitution” refers to the replacement of one amino acid residue by a different amino acid residue.

[0062] As used herein, the term “conservative amino acid substitution” is defined herein as exchanges within one of the following five groups: I. Small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, Gly; II. Polar, negatively charged residues and their amides: Asp, Asn, Glu, Gln; III. Polar, positively charged residues: His, Arg, Lys; Ornithine (Orn); IV. Large, aliphatic, nonpolar residues: Met, Leu, Ile, Val, Cys, Norleucine (Nle), homocysteine (hCys); V. Large, aromatic residues: Phe, Tyr, Trp, acetyl phenylalanine, napthylalanine (Nal).

[0063] As used herein the general term “polyethylene glycol chain” or “PEG chain”, refers to mixtures of condensation polymers of ethylene oxide and water, in a branched or straight chain, represented by the general formula H(OCH2CH2)kOH, wherein k is at least 2.

[0064] As used herein the term “miniPEG” or “OEG” defines a functionalized polyethylene compound comprising the structure:.

[0065] As used herein the term “pegylated” and like terms refers to a compound that has been modified from its native state by linking a polyethylene glycol chain to the compound. A “pegylated polypeptide” is a polypeptide that has a PEG chain covalently bound to the polypeptide.

[0066] As used herein a “linker” or “spacer” is a bond, molecule or group of molecules that binds two separate entities to one another. Linkers may provide for optimal spacing of the two entities or may further supply a labile linkage that allows the two entities to be separated from each other. Labile linkages include photocleavable groups, acid-labile moieties, base-labile moieties, and enzyme-cleavable groups.

[0067] As used herein a “dimer” is a complex comprising two subunits covalently bound to one another via a linker. The term dimer, when used absent any qualifying language, encompasses both homodimers and heterodimers. A homodimer comprises two identical subunits, whereas a heterodimer comprises two subunits that differ, although the two subunits are substantially similar with one another.

[0068] The term “C1-Cnalkyl” wherein n can be from 1 through 6, as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso- butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

[0069] As used herein the term C16-C20 fatty acid designates the structure: —CO(CH2)14-18CH3 and the term C16-C20 diacid designates the structure: —CO(CH2)14-18COOH, wherein the prefix “C16-C20” designates the variable total number of carbons in the compounds encompassed by the designation. For example, a C18 diacid represents the structure: —CO(CH2)16COOH. As used herein a generic reference to an acylated amino acid encompasses both an amino acid having its side chain acylated with a fatty acid and an amino acid having its side chain acylated with a diacid.

[0070] Physiological conditions as disclosed herein are intended to include a temperature of about 35 to 40° C. and a pH of about 7.0 to about 7.4, and more typically include a pH of 7.2 to 7.4 and a temperature of 36 to 38° C. Since physiological pH and temperature are tightly regulated in humans within a highly defined range, the speed of conversion from dipeptide / drug complex (prodrug) to drug will exhibit high intra and interpatient reproducibility.

[0071] The term “about” as used herein means greater or lesser than the value or range of values stated by 10 percent but is not intended to limit any value or range of values to only this broader definition. ABBREVIATIONS

[0072] Lower case k = d-isomer of lysine

[0073] γE = 1-isomer of gamma, glutamic acid

[0074] (miniPEG)2= COCH2OCH2CH2OCH2CH2NH

[0075] COC16H32CO2H = (C18 diacid)

[0076] (N—Me)G = sarcosine

[0077] Upper case K = 1-isomer of lysine COMPOUNDS In an aspect, the present disclosure provides a compound 1. In some cases, compound 1 is represented by: 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 gamma, glutamic acid; (miniPEG)2 is COCH2OCH2CH2OCH2CH2NH; COC16H32CO2H is C18 diacid; and (N- Me)G is sarcosine. In some cases, compound is represented by PTH(1-33), dK-1(γE-2xOEG-γE- diacidC18), N(Me)G0, K33(γE-2xOEG-γE-diacidC18). 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 the cleavage of SEQ ID NO: 1. In some cases, SEQ ID NO: 2 is formed by the in vivo cleavage of SEQ ID NO: 1.

[0078] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0079] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0080] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:.

[0081] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure 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 the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0082] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0083] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0084] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0085] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: 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.

[0086] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0087] 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, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0088] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0089] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0090] As used herein, the term “prodrug” is defined as any compound that undergoes chemical modification before exhibiting its pharmacological effects.

[0091] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0092] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., 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, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0093] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. 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). Pharmaceutical Formulations

[0094] In an aspect, the present disclosure provides a pharmaceutical composition includes SEQ ID NO: 1. In some cases, a pharmaceutical composition includes SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration. In some cases, a pharmaceutical composition includes SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week. In some embodiments, a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 2 has a half-life of greater than about 100 hours. In some cases, a pharmaceutical composition includes SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 2 has a release half-life of greater than about 100 hours. In some cases, a pharmaceutical composition includes SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 2 has a release half- life of greater than about 100 hours and wherein SEQ ID NO: 1 has a half-life of greater than about 70 hours. In some cases, SEQ ID NO: 1 converts into SEQ ID NO: 2. In some cases, SEQ ID NO: 1 converts into SEQ ID NO: 2 after in vivo. In some cases, SEQ ID NO: 1 converts into SEQ ID NO: 2 after in vivo cleavage. In some cases, SEQ ID NO: 1 converts into SEQ ID NO: 2 via intramolecular self-cleavage. In some cases, SEQ ID NO: 1 converts into SEQ ID NO: 2 after the diketopiperazine cyclization. In some cases, SEQ ID NO: 1 converts into SEQ ID NO: 2 after in vivo 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 about 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 about 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 from about 100 hours to about 500 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 100 hours to about 300 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 100 hours to about 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 100 hours to about 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 150 hours to about 500 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 150 hours to about 300 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 150 hours to about 250 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 150 hours to about 200 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 150 hours to about 180 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 150 hours to about 160 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 100 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 120 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is from about 130 hours to about 150 hours. In some cases, the release half-life of SEQ ID NO: 2 is from 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 from about 100 hours to about 500 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 100 hours to about 300 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 100 hours to about 250 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 100 hours to about 200 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 150 hours to about 500 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 150 hours to about 300 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 150 hours to about 250 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 150 hours to about 200 hours. In some cases, the half- life of SEQ ID NO: 2 is from about 150 hours to about 180 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 150 hours to about 160 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 100 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 120 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is from about 130 hours to about 150 hours. In some cases, the half-life of SEQ ID NO: 2 is from 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, SEQ ID NO: 1 has a half-life of about 60 hours. In some cases, SEQ ID NO: 1 has a half-life of about 70 hours. In some cases, SEQ ID NO: 1 has a half-life of about 80 hours. In some cases, SEQ ID NO: 1 has a half-life of about 85 hours. In some cases, SEQ ID NO: 1 has a half-life of about 90 hours. In some cases, SEQ ID NO: 1 has a half-life of about 95 hours. In some cases, SEQ ID NO: 1 has a half-life of about 100 hours. In some cases, SEQ ID NO: 1 has a half-life of greater than about 60 hours. In some cases, SEQ ID NO: 1 has a half-life of greater than about 70 hours. In some cases, SEQ ID NO: 1 has a half-life of greater than about 80 hours. In some cases, SEQ ID NO: 1 has a half-life of greater than about 85 hours. In some cases, SEQ ID NO: 1 has a half-life of greater than about 90 hours. In some cases, SEQ ID NO: 1 has a half- life of greater than about 95 hours. In some cases, SEQ ID NO: 1 has a half-life of less than about 120 hours. In some cases, SEQ ID NO: 1 has a half-life of less than about 100 hours. In some cases, SEQ ID NO: 1 has a half-life of less than the release half-life of SEQ ID NO: 2. In some cases, for the same dose, SEQ ID NO: 1 has a half-life of less 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, a dose comprises the pharmaceutical composition, wherein the dose is from about 200 μg to 900 μg. In some cases, a dose comprises the pharmaceutical composition, wherein the dose is about 200 μg. In some cases, a dose comprises the pharmaceutical composition, wherein the dose is about 400 μg. In some cases, a dose comprises the pharmaceutical composition, wherein the dose is about 600 μg. In some cases, a dose comprises the pharmaceutical composition, wherein the dose is about 900 μg. In some cases, the SEQ ID NO: 1 has a time to peak drug concentration (tmax) of at least about 35 hours. In some cases, the SEQ ID NO: 1 has a tmaxof at least about 40 hours. In some cases, the SEQ ID NO: 1 has a tmaxof at least about 45 hours. In some cases, the SEQ ID NO: 1 has a tmax of less than about 60 hours. In some cases, the SEQ ID NO: 1 has a tmax of less than about 55 hours. In some cases, the SEQ ID NO: 1 has a tmax of less than about 50 hours. In some cases, the SEQ ID NO: 2 has a tmax of at least about 45 hours. In some cases, the SEQ ID NO: 2 has a tmaxof at least about 50 hours. In some cases, the SEQ ID NO: 2 has a tmaxof at least about 55 hours. In some cases, the SEQ ID NO: 2 has a tmax of at least about 60 hours. In some cases, the SEQ ID NO: 2 has a tmax of at least about 65 hours. In some cases the SEQ ID NO: 2 has a tmax of at least about 67 hours. In some cases, the SEQ ID NO: 2 has a tmaxof at less than about 75 hours. In some cases, the SEQ ID NO: 2 has a tmax of at less than about 70 hours. In some cases, the SEQ ID NO: 2 has a tmax of at less than about 65 hours. In some cases, the SEQ ID NO: 2 has a tmax of at less than about 60 hours. In some cases, the SEQ ID NO: 2 has a tmaxof at less than about 55 hours. In some cases, the SEQ ID NO: 1 has a tmax of at least about 35 hours and the SEQ ID NO: 2 has a tmax of at least about 45 hours. In some cases, the SEQ ID NO: 2 has an AUC of at least about 100 hours for a dose comprising SEQ ID NO: 2 of about 200 μg. In some cases, the SEQ ID NO: 2 has an AUC of at least about 180 hours for a dose comprising SEQ ID NO: 2 of about 400 μg. In some cases, the SEQ ID NO: 2 has an AUC of at least about 320 hours for a dose comprising SEQ ID NO: 2 of about 600 μg. In some cases, the SEQ ID NO: 2 has an AUC of at least about 420 hours for a dose comprising SEQ ID NO: 2 of about 900 μg. In some cases, the does may be as described elsewhere herein. In some cases, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some cases, the half-life is a circulation half-life. In some cases, the half-life is a circulation half-life in a subject. In some cases, the release half-life is the time it takes for the concentration or amount in the subject of the compound to be reduced by exactly one-half (50%).

[0095] In some embodiments, the release half-life (t½) is the time it takes for the concentration or amount in the subject of that drug (e.g., SEQ ID NO: 2) to be reduced by exactly one-half (50%).

[0096] In some embodiments, compound 1 is considered a prodrug. In some cases, compound 2 is considered the active drug. In some cases, compound 2 is an active drug formed from compound 1.

[0097] In some embodiments, a conjugate is represented by A-B-Q, where A-B-Q is k(γE- (miniPEG)2-γE-COC16H32CO2H)(N-Me)GSVSEIQLMHNLGKHLNSMER VEWLRKKLQDVHK(γE-(miniPEG)2-γE-COC16H32CO2H)-OH. In some cases, A-B is a self- cleaving dipeptide. In some cases, A-B 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, A-B-Q is converted into A-B and Q. In some cases, A-B dissociates via a cyclization pathway, where A-B forms a cyclic compound leaving behind Q (e.g., compound 2). In some cases, the cyclization occurs at physiological pH. In some cases, the cyclization occurs at about pH 7.4. In some cases, the chemical cleavage half-life (t1 / 2) of A-B from A-B-Q 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.

[0098] In some embodiments, compound 1 is represented by (SEQ ID NO: 1)

[0099] In some embodiments, compound 2 (SEQ ID NO: 2) is represented by.

[0100] Provided herein, in certain embodiments, are 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 one thereof (also referred to herein as “a pharmaceutical agent”).

[0101] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0102] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain 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 the pharmaceutical 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 vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0103] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0104] A pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0105] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0106] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0107] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500- 1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0108] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0109] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0110] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0111] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0112] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0113] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0114] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase 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, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0115] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0116] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0117] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0118] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ^. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ^ range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb ^ ^ and AeroDose ^ ^ ^vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ^ nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC ^ and Pari LC Star ^ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ^ ^ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire ^ (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0119] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0120] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.

[0121] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0122] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.

[0123] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0124] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.

[0125] In some embodiments, the kit is provided with a device for administering compound 1 (SEQ ID NO: 1) or a pharmaceutical composition comprising compound 1 to a patient. The kit may further include a variety of containers, e.g., vials, tubes, bottles, and the like. Preferably, the kits will also include instructions for use. In some cases, the device of the kit is an aerosol dispensing device, wherein the composition is prepackaged within the aerosol device. In some cases, the kit comprises a syringe and a needle, and in some embodiments, compound 1 or a pharmaceutical composition comprising compound 1 is prepackaged within the syringe or injection pen, using a low gauge needle, for example having a 29-31 size.

[0126] In some embodiments, a pharmaceutical composition comprising SEQ ID NO: 1 is suitable for subcutaneous administration. In some cases, a pharmaceutical composition comprising SEQ ID NO: 1 is suitable for once a week subcutaneous administration.

[0127] In some embodiments, a pharmaceutical composition comprising compound 1, wherein the pharmaceutical composition is suitable for once a week subcutaneous administration, wherein after administration of compound 2, a pharmacokinetic profile of compound 2 exhibits a peak to trough ratio of less than about 2 in plasma. In some embodiments, a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for once a week subcutaneous administration, wherein after administration of SEQ ID NO: 1, a pharmacokinetic profile of SEQ ID NO: 2 exhibits a peak to trough ratio of less than about 2 in plasma. In some cases, the peak to trough ratio is less than about 1.8 in plasma. In some cases, the peak to trough ratio is less than about 1.6 in plasma. In some cases, the peak to trough ratio is greater than about 1.1 in plasma. In some cases, the peak to trough is greater than about 1.2 in plasma. In some cases, the peak to trough ratio is about 1.3 in plasma. In some cases, the peak to trough ratio is about 1.4 in plasma. In some cases, the peak to trough ratio is about 1.5 in plasma. In some cases, the peak to trough ratio is about 1.6 in plasma. In some cases, the peak to trough ratio is about 1.7 in plasma. In some cases, the peak to trough ratio is about 1.8 in plasma. In some cases, the peak to trough ratio is about 1.9 in plasma. In some cases, the peak to trough ratio is about 2 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.8 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.7 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.6 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.5 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.4 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.3 in plasma. In some cases, the peak to trough ratio is from about 1.1 to about 1.2 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.8 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.7 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.6 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.5 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.4 in plasma. In some cases, the peak to trough ratio is from about 1.2 to about 1.3 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 1.8 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 1.7 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 1.6 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 1.5 in plasma. In some cases, the peak to trough ratio is from about 1.3 to about 1.4 in plasma. In some cases, the peak to trough ratio is from about 1.4 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.4 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.4 to about 1.8 in plasma. In some cases, the peak to trough ratio is from about 1.4 to about 1.7 in plasma. In some cases, the peak to trough ratio is from about 1.4 to about 1.6 in plasma. In some cases, the peak to trough ratio is from about 1.4 to about 1.5 in plasma. In some cases, the peak to trough ratio is from about 1.5 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.5 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.5 to about 1.8 in plasma. In some cases, the peak to trough ratio is from about 1.5 to about 1.7 in plasma. In some cases, the peak to trough ratio is from about 1.5 to about 1.6 in plasma. In some cases, the peak to trough ratio is from about 1.6 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.6 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.6 to about 1.8 in plasma. In some cases, the peak to trough ratio is from about 1.6 to about 1.7 in plasma. In some cases, the peak to trough ratio is from about 1.7 to about 2 in plasma. In some cases, the peak to trough ratio is from about 1.7 to about 1.9 in plasma. In some cases, the peak to trough ratio is from about 1.7 to about 1.8 in plasma. In some cases, the peak to trough ratio is measured at steady state after a subcutaneous administration of the pharmaceutical composition. In some cases, steady-state is the point at which the input mass of compound 2 is equivalent to the mass eliminated from the body by clearance during any unit of time. In some cases, steady-state is the point at which the input mass of compound 2 is equivalent to the mass eliminated from the body by clearance before 300 hours.

[0128] In some cases, the peak to trough ratio is measured before about 250 hours after a subcutaneous administration of the pharmaceutical composition. In some cases, the peak to trough ratio is measured before about 200 hours after a subcutaneous administration of the pharmaceutical composition. In some cases, the peak to trough ratio is measured about 48 hours after a subcutaneous administration of the pharmaceutical composition. In some cases, the subcutaneous administration is via subcutaneous injection. In some cases, the subcutaneous administration occurs with a pen device. In some cases, the administration is to a non-human primate. In some cases, the administration is to a monkey. In some cases, the administration is to a mouse. In some cases, the administration is to a human.

[0129] In some embodiments, pharmaceutical compositions are 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, pharmaceutical compositions are 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, a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 2 has a maximum plasma concentration (Cmax) of at most about 6 (nmol / L), when a dose comprising the SEQ ID NO: 1 is administered to the subject, wherein the dose is between 200 μg to 900 μg. The does may be as described elsewhere herein. In some cases, SEQ ID NO: 2 is formed by the cleavage of SEQ ID NO: 1

[0130] In some embodiments, a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 2 has a maximum plasma concentration (Cmax) of at least about 0.4 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 0.6 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 0.8 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.2 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.3 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.4 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.5 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.6 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.7 (nmol / L). In some cases, the maximum plasma concentration (Cmax) is at least about 1.8 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 1.9 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.1 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.2 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.3 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.4 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.5 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.6 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.7 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.8 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 2.9 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 3.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 3.1 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at least about 3.2 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 5.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 4.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.9 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.8 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.7 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.6 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.5 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.4 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.3 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.2 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.1 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 3.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 2.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 0.6 (nmol / L) to 4.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 0.8 (nmol / L) to 3.2 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 0.8 (nmol / L) to 2.4 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 0.8 (nmol / L) to 1.3 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 0.8 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 1.3 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 2.4 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is from about 3.2 (nmol / L).

[0131] In some embodiments, a pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 1 has a maximum plasma concentration (Cmax) of at least about 2.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 3.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 4.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 5.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 6.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 7.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 8.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 9.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 10.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 11.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 12.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 13.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 14.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 15.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 16.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 17.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at most about 20.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 19.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 19.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 18.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 17.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 16.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1is at least about 15.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 14.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 13.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 12.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 11.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 10.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 9.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 8.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 7.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 6.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 5.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 4.0 (nmol / L). In some cases, the maximum plasma concentration (Cmax) of SEQ ID NO: 1 is at least about 3.0 (nmol / L). In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is at least about 4. In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is at most about 6. In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4. In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4.2. In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is about 5.4. In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is about 5.5. In some cases, the ratio of Cmax of SEQ ID NO: 1 to SEQ ID NO: 2 is about 4 to about 6. Methods of Treatment

[0132] In an aspect, the present disclosure provides a method of treating a subject with hypoparathyroidism, osteoporosis, or osteopenia, comprising administering to the subject once a week a dose of at least about 30 micrograms (μg), wherein the dose comprises SEQ ID NO: 1. In some embodiments, is provided a method of treating a subject with hypoparathyroidism, osteoporosis, or osteopenia, comprising administering to the subject once a week a dose of at least about 30 μg, wherein the dose comprises a pharmaceutical composition comprising SEQ ID NO: 1. In some embodiments, is provided a method of treating a subject with hypoparathyroidism, comprising administering to the subject once a week a dose of at least about 30 μg, wherein the dose comprises a pharmaceutical composition comprising SEQ ID NO: 1. In some embodiments, is provided a method of treating a subject with hypoparathyroidism, comprising administering to the subject once a week a dose of at least about 30 μg, wherein the dose comprises a pharmaceutical composition comprising SEQ ID NO: 1, and wherein SEQ ID NO: 2 has a release half-life of greater than about 100 hours. In some cases, the dose is at least about 50 μg. In some cases, dose is at least about 100 μg. In some cases, dose is at least about 200 μg. In some cases, dose is at least about 300 μg. In some cases, the dose is at least about 400 μg. In some cases, dose is at least about 500 μg. In some cases, 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 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. In some cases, the dose is about 50 µg. In some cases, the dose is about 150 µg. In some cases, the dose is about 200 µg. In some cases, the dose is about 300 µg. In some cases, the dose is about 400 µg. In some cases, the dose is about 460 µg. In some cases, dose is about 600 µg. In some cases, the dose is about 900 µg. In some cases, the dose is less than about 1000 µg. In some cases, the dose is less than about 900 µg. In some cases, the dose is less than 600 µg. In some cases, the dose is from about 30 μg to 1000 μg. In some cases, the dose is from about 30 μg to 900 μg. In some cases, the dose is from about 30 μg to 800 μg. In some cases, the dose is from about 30 μg to 700 μg. In some cases, the dose is from about 30 μg to 600 μg. In some cases, the dose is from about 30 μg to 500 μg. In some cases, the dose is from about 30 μg to 400 μg. In some cases, the dose is from about 30 μg to 300 μg. In some cases, the dose is from about 30 μg to 200 μg. In some cases, the dose is from about 30 μg to 100 μg. In some cases, the dose is from about 30 μg to 50 μg. In some cases, the dose is from about 50 μg to 1000 μg. In some cases, the dose is from about 50 μg to 900 μg. In some cases, the dose is from about 50 μg to 800 μg. In some cases, the dose is from about 50 μg to 700 μg. In some cases, the dose is from about 50 μg to 600 μg. In some cases, the dose is from about 50 μg to 500 μg. In some cases, the dose is from about 50 μg to 460 μg. In some cases, the dose is from about 50 μg to 400 μg. In some cases, the dose is from about 50 μg to 300 μg. In some cases, the dose is from about 50 μg to 200 μg. In some cases, the dose is from about 50 μg to 100 μg. In some cases, the dose is from about 50 μg to 75 μg. In some cases, the dose is from about 100 μg to 1000 μg. In some cases, the dose is from about 100 μg to 900 μg. In some cases, the dose is from about 100 μg to 800 μg. In some cases, the dose is from about 100 μg to 700 μg. In some cases, the dose is from about 100 μg to 600 μg. In some cases, the dose is from about 100 μg to 500 μg. In some cases, the dose is from about 100 μg to 460 μg. In some cases, the dose is from about 100 μg to 400 μg. In some cases, the dose is from about 100 μg to 300 μg. In some cases, the dose is from about 100 μg to 200 μg. In some cases, the dose is from about 100 μg to 100 μg. In some cases, the dose is from about 100 μg to 75 μg. In some cases, the dose is from about 200 μg to 1000 μg. In some cases, the dose is from about 200 μg to 900 μg. In some cases, the dose is from about 200 μg to 800 μg. In some cases, the dose is from about 200 μg to 700 μg. In some cases, the dose is from about 200 μg to 600 μg. In some cases, the dose is from about 200 μg to 500 μg. In some cases, the dose is from about 200 μg to 460 μg. In some cases, the dose is from about 200 μg to 400 μg. In some cases, the dose is from about 200 μg to 300 μg. In some cases, the dose is from about 300 μg to 1000 μg. In some cases, the dose is from about 300 μg to 900 μg. In some cases, the dose is from about 300 μg to 800 μg. In some cases, the dose is from about 300 μg to 700 μg. In some cases, the dose is from about 300 μg to 600 μg. In some cases, the dose is from about 300 μg to 500 μg. In some cases, the dose is from about 300 μg to 460 μg. In some cases, the dose is from about 300 μg to 400 μg. In some cases, the dose is from about 400 μg to 1000 μg. In some cases, the dose is from about 400 μg to 900 μg. In some cases, the dose is from about 400 μg to 800 μg. In some cases, the dose is from about 400 μg to 700 μg. In some cases, the dose is from about 400 μg to 600 μg. In some cases, the dose is from about 400 μg to 500 μg. In some cases, the dose is from about 400 μg to 460 μg. In some cases, the dose is from about 460 μg to 1000 μg. In some cases, the dose is from about 460 μg to 900 μg. In some cases, the dose is from about 460 μg to 800 μg. In some cases, the dose is from about 460 μg to 700 μg. In some cases, the dose is from about 460 μg to 600 μg. In some cases, the dose is from about 460 μg to 500 μg. In some cases, the dose is from about 500 μg to 1000 μg. In some cases, the dose is from about 500 μg to 900 μg. In some cases, the dose is from about 500 μg to 800 μg. In some cases, the dose is from about 500 μg to 700 μg. In some cases, the dose is from about 500 μg to 600 μg. In some cases, the dose is from about 600 μg to 1000 μg. In some cases, the dose is from about 600 μg to 900 μg. In some cases, the dose is from about 600 μg to 800 μg. In some cases, the dose is from about 600 μg to 700 μg. In some cases, the dose is from about 700 μg to 1000 μg. In some cases, the dose is from about 700 μg to 900 μg. In some cases, the dose is from about 700 μg to 800 μg. In some cases, the method is for treating hypoparathyroidism in a subject in need thereof. In some cases, the method is for treating osteoporosis, or osteopenia, in a subject in need thereof. 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 once a week, for 5 weeks. In some cases, the dose is administered once a week, for 6 weeks. In some cases, the dose is administered once a week, for 7 weeks. In some cases, the dose is administered once a week, for 8 weeks. In some cases, the dose is administered once a week, for 9 weeks. In some cases, the dose is administered once a week, for 10 weeks. In some cases, the dose is administered once a week, for 11 weeks. In some cases, the dose is administered once a week, for 12 weeks. In some cases, the dose is administered once a week, for 13 weeks. In some cases, the dose is administered once a week, for 14 weeks. In some cases, the dose is administered once a week, for 15 weeks. In some cases, the dose is administered once a week, for 16 weeks. In some cases, the dose is administered once a week, for 17 weeks. In some cases, the dose is administered once a week, for 18 weeks. In some cases, the dose is administered once a week, for 19 weeks. In some cases, the dose is administered once a week, for 20 weeks. In some cases, the dose is administered once a week, for 21 weeks. In some cases, the dose is administered once a week, for 22 weeks. In some cases, the dose is administered once a week, for 23 weeks. In some cases, the dose is administered once a week, for 24 weeks. In some cases, the dose is administered once a week, for 25 weeks. In some cases, the dose is administered once a week, for 26 weeks. In some cases, the dose is administered once a week, for 27 weeks. In some cases, the dose is administered once a week, for 28 weeks. In some cases, the dose is administered once a week, for 29 weeks. In some cases, the dose is administered once a week, for 30 weeks. In some cases, the dose is administered once a week, for 31 weeks. In some cases, the dose is administered once a week, for 32 weeks. In some cases, the dose is administered once a week, for 33 weeks. In some cases, the dose is administered once a week, for 34 weeks. In some cases, the dose is administered once a week, for 35 weeks. In some cases, the dose is administered once a week, for 36 weeks. In some cases, the dose is administered once a week, for 37 weeks. In some cases, the dose is administered once a week, for 38 weeks. In some cases, the dose is administered once a week, for 39 weeks. In some cases, the dose is administered once a week, for 40 weeks. In some cases, the dose is administered once a week, for 41 weeks. In some cases, the dose is administered once a week, for 42 weeks. In some cases, the dose is administered once a week, for 43 weeks. In some cases, the dose is administered once a week, for 44 weeks. In some cases, the dose is administered once a week, for 45 weeks. In some cases, the dose is administered once a week, for 46 weeks. In some cases, the dose is administered once a week, for 47 weeks. In some cases, the dose is administered once a week, for 48 weeks. In some cases, the dose is administered once a week, for 49 weeks. In some cases, the dose is administered once a week, for 50 weeks. In some cases, the dose is administered once a week, for 51 weeks. In some cases, the dose is administered once a week, for 52 weeks. In some cases, the dose is administered once a week, for 1 year. In some cases, the dose is administered once a week, for 2 years. In some cases, the dose is administered once a week, for 3 years. In some cases, the dose is administered once a week, for 4 years. In some cases, the dose is administered once a week, for 5 years.

[0133] In some embodiments, the dose is administered once a week for 8 weeks at a fixed dose, followed by a four-week titration period. In some cases, the fixed dose is about 400 µg to about 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. In the four-week titration period is an up-titration for subjects unable to discontinue active vitamin D and / or reduce calcium supplements.

[0134] In some embodiments, the present disclosure provides a method of treating a subject with disease or conditions associated with insufficient levels of PTH (hypoparathyroidism), or disease responsive to PTH therapy such as osteoporosis, comprising administering to the subject once a week a dose of at least about 30 μg, wherein the dose comprises SEQ ID NO: 1. In some cases, the quantity of the dose may be as described elsewhere herein. In some cases, a method of treating hypoparathyroidism is provided wherein a patient in need of such therapy is administered compound 1 (SEQ ID NO: 1) in accordance with any of those described herein in an amount effective to treat or prevent hypoparathyroidism or alleviate a medical condition associated with hypoparathyroidism.

[0135] In some embodiments, the subject in need of treatment has osteoporosis. In some embodiments, the subject in need of treatment has osteopenia. In cases, the subject in need of treatment is a post-menopausal woman. In cases, the subject in need of treatment has glucocorticoid induced osteoporosis. In cases, the subject in need of treatment has glucocorticoid induced osteopenia.

[0136] In some embodiments, a method of treatment of osteoporosis is provided comprising treating a subject in need thereof by weekly subcutaneous injection with compound 1 (SEQ ID NO: 1) of the present disclosure.

[0137] In some embodiments, a method of treatment of renal impairment is provided comprising treating a subject in need thereof by weekly subcutaneous injection with compound 1 (SEQ ID NO: 1) of the present disclosure.

[0138] In some embodiments, a method of treatment of kidney failure is provided comprising treating a subject in need thereof by weekly subcutaneous injection with compound 1 (SEQ ID NO: 1) of the present disclosure.

[0139] In another embodiment this disclosure provides a method of treatment of osteoporosis comprising treating a subject in need thereof by weekly subcutaneous injection with compound 1 (SEQ ID NO: 1) of the present disclosure.

[0140] In some embodiments, telopeptides of type 1 collagen can be used as bone resorption biomarkers. In some cases, the bone resorption biomarker is selected from carboxy-terminal crosslinked (CTX-1) and amino-terminal crosslinked (NTX-1). In some cases, CTX-1 and NTX- 1 are both are released during collagen degradation. In some cases, ELISA can be used to measured CTX-1 with a monoclonal antibody against an octapeptide sequence (EKAHD-β-GGR) in the α-1 (I) chain of the β-isoform. In some cases, CTX-1 is a specific and sensitive biomarker of bone resorption that can rapidly indicate the response to bisphosphonate therapy for postmenopausal osteoporosis. In some cases, serum CTX-1 is influenced by food intake and blood withdrawal must take place in the fasting state because food intake substantially decreases the levels of CTX-1.

[0141] In some embodiments, is provided a method of treating a subject with hypoparathyroidism, comprising: (a) determining a level of CTX-1 of the subject upon once a week administration of SEQ ID NO: 1 to the subject, and (b) providing continued once a week administration of SEQ ID NO: 1 to the subject, wherein the level of CTX-1 is less than about 900 pg / mL. In some cases, the level of CTX-1 is less than about 850 pg / mL. In some cases, the level of CTX-1 is less than about 800 pg / mL. In some cases, the level of CTX-1 is less than about 700 pg / mL. In some cases, the level of CTX-1 is less than about 600 pg / mL. In some cases, the level of CTX-1 is less than about 500 pg / mL. In some cases, the level of CTX-1 is less than about 450 pg / mL. In some cases, the level of CTX-1 is less than about 400 pg / mL. In some cases, the level of CTX-1 is less than about 300 pg / mL. In some cases, the level of CTX-1 is less than about 200 pg / mL. In some cases, the level of CTX-1 is more than about 100 pg / mL. In some cases, the level of CTX-1 is more than about 200 pg / mL. In some cases, the level of CTX-1 is more than about 300 pg / mL. In some cases, the level of CTX-1 is more than about 400 pg / mL. In some cases, the level of CTX-1 is more than about 500 pg / mL. In some cases, the level of CTX-1 is more than about 600 pg / mL. In some cases, the level of CTX-1 is more than about 700 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 1000 pg / mL. In some cases, the level of CTX- 1 is from about 50 pg / mL to about 900 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 800 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 700 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 600 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 500 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 400 pg / mL. In some cases, the level of CTX-1 is from about 50 pg / mL to about 300 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 1000 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 900 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 800 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 700 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 600 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 500 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 400 pg / mL. In some cases, the level of CTX-1 is from about 200 pg / mL to about 300 pg / mL. In some cases, the level of CTX-1 is from about 300 pg / mL to about 1000 pg / mL. In some cases, the level of CTX-1 is from about 300 pg / mL to about 900 pg / mL. In some cases, the level of CTX-1 is from about 300 pg / mL to about 800 pg / mL. In some cases, the level of CTX-1 is from about 300 pg / mL to about 700 pg / mL. In some cases, the level of CTX-1 is from about 300 pg / mL to about 600 pg / mL. In some cases, the level of CTX-1 is from about 300 pg / mL to about 500 pg / mL. In some cases, the level of CTX-1 is from about 500 pg / mL to about 1000 pg / mL. In some cases, the level of CTX-1 is from about 500 pg / mL to about 900 pg / mL. In some cases, the level of CTX-1 is from about 500 pg / mL to about 800 pg / mL. In some cases, the level of CTX-1 is from about 500 pg / mL to about 700 pg / mL. In some cases, the level of CTX-1 is from about 500 pg / mL to about 600 pg / mL. In some cases, the dosage of SEQ ID NO: 1 is no greater than 1000 μg once a week. In some cases, the dosage of SEQ ID NO: 1 is as described elsewhere herein once a week. In some cases, determining further comprises 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 comprising (c), administering to the subject a therapeutically effective amount of an anti-resorptive medication. In some cases, the CTX-1 level is measured between 1 to 30 days. In some cases, the CTX-1 level is measured between 1 to 15 days. In some cases, the CTX-1 level is measured between 15 to 30 days. In some cases, the CTX-1 level is measured between 12 to 25 days. In some cases, a dose of 200 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of CTX-1 in the subject. In some cases, a dose of 400 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of CTX-1 in the subject. In some cases, a dose of 600 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of CTX-1 in the subject. In some cases, a dose of 900 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of CTX-1 in the subject. In some cases, the CTX-1 level is measured using ELISA.

[0142] In some embodiments, type 1 collagen can be found in the organic bone matrix (> 90%), which is developed in bone from procollagen type 1. In some cases, procollagen type 1 is synthesized by fibroblasts and osteoblasts. In some cases, procollagen type 1 has N-terminal and C-terminal extensions, which are removed by specific proteases during conversion of procollagen to collagen. In some cases, the procollagen type 1 included P1CP and P1NP are subsequently conjugated onto the bone matrix. In some cases, the bone formation biomarker of P1NP is a specific indicator of type 1 collagen deposition. In some cases, P1NP is released during the formation of type 1 collagen into the intracellular space and P1NP eventually exists in the blood stream. In some cases, P1NP is usually released in the trimeric structure (derived from the trimeric collagen structure) and then is rapidly broken down to a monomeric form by thermal degradation effects. In some cases, antibodies of P1NP are used to detect the trimeric structure of P1NP by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. In some cases, P1NP has been demonstrated to be a more sensitive bone biomarker to measure the bone formation rate in osteoporosis.

[0143] In some embodiments, is provided a method of treating a subject with hypoparathyroidism, comprising: (a) determining a level of Procollagen type I N-terminal propeptide (P1NP) of the subject upon weekly administration of SEQ ID NO: 1 to the subject, and (b) providing continued once a week administration of SEQ ID NO: 1 to the subject, wherein the level of P1NP is greater than about -50 μg / L in the subject. In some cases, the level of P1NP is greater than about -40 μg / L in the subject. In some cases, the level of P1NP is greater than about -30 μg / L in the subject. In some cases, the level of P1NP is greater than about -20 μg / L in the subject. In some cases, the level of P1NP is greater than about -10 μg / L in the subject. In some cases, the level of P1NP is less than about -30 μg / L in the subject. In some cases, the level of P1NP is less about -20 μg / L in the subject. In some cases, the level of P1NP is less than about - 10 μg / L in the subject. In some cases, the level of P1NP is less than about -5 μg / L in the subject. In some cases, the level of P1NP is from about -5 μg / L to -50 μg / L. In some cases, the level of P1NP is from about -5 μg / L to -40 μg / L. In some cases, the level of P1NP is from about -5 μg / L to -30 μg / L. In some cases, the level of P1NP is from about -5 μg / L to -20 μg / L. In some cases, the level of P1NP is from about -5 μg / L to -10 μg / L. In some cases, the level of P1NP is from about -10 μg / L to -50 μg / L. In some cases, the level of P1NP is from about -10 μg / L to -40 μg / L. In some cases, the level of P1NP is from about -10 μg / L to -30 μg / L. In some cases, the level of P1NP is from about -10 μg / L to -20 μg / L. In some cases, the level of P1NP is from about -20 μg / L to -50 μg / L. In some cases, the level of P1NP is from about -20 μg / L to -40 μg / L. In some cases, the level of P1NP is from about -20 μg / L to -30 μg / L. In some cases, the P1NP level is measured between 1 to 30 days. In some cases, the P1NP level is measured between 1 to 15 days. In some cases, the P1NP level is measured between 15 to 30 days. In some cases, the P1NP level is measured between 12 to 25 days. In some cases, a dose of 200 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of P1NP in the subject. In some cases, a dose of 400 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of P1NP in the subject. In some cases, a dose of 600 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of P1NP in the subject. In some cases, a dose of 900 μg, wherein the dose comprises SEQ ID NO: 1 is administered to the subject prior to determining a level of P1NP in the subject. In some cases, the level of P1NP is measured using an Elecsys 2010 automated analyzer.

[0144] In some embodiments, any one of the methods described herein results in an increase in serum calcium levels of the subject. In some cases, serum calcium is assessed by the maximal increase in serum calcium (Emax,adj). In some cases, serum calcium is assess by total serum calcium levels between injections (AUEC0-τ, adj). In some cases, maximal increases in albumin-adjusted serum calcium is observed approximately 48 hours after injection. In some cases, increases in serum calcium are nearly maximal after a third weekly injection.

[0145] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound (e.g., compound 1) described herein, or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0146] The compounds described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0147] In some embodiments, a compound of the disclosure (e.g., compound 1) may be administered alone or in combination with other agents, for example, bone antiresorptive agents, including calcitonin, bisphosphonates, SERMs (e.g. raloxifene), hormone replacement therapy (HRT), calcium, Vitamin D1, Vitamin D2, Vitamin D3, Vitamin D4 and estrogen. A compound of this disclosure may be co-administered with another agent. Alternatively, a compound of this disclosure may be administered sequentially with another agent; for example a compound of this disclosure is administered alone for a period from one week to one year followed by administration of another agent, either together with said compound or in the absence of said compound.

[0148] In prophylactic applications, compositions containing the compounds described herein are administered to a subject susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the subject's state of health, weight, and the like. When used in a subject, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.

[0149] In the case wherein the subject’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the subject’s life in order to ameliorate or otherwise control or limit the symptoms of the subject’s disease or condition.

[0150] Once improvement of the subject's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Subjects can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0151] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0152] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple- dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0153] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0154] In certain embodiments, the invention provides a method of treating or preventing a disease, state, or condition in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein.

[0155] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES

[0156] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. Example 1: Synthesis Procedures

[0157] Compound 1 (SEQ ID NO: 1) was synthesized using analogous synthetic procedures as shown in WO2021242756A2 (PCT / US2021 / 034055) and US20230285578A1. Table 1: Compounds with SEQ ID NOsExample 2: A Phase 1, Randomized, Double Blind, Placebo Controlled, Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single and Multiple Ascending Doses of Compound 1 in Healthy Participants.

[0191] Compound 1 (SEQ ID NO: 1) was investigated as a potential therapy for treatment of hypoparathyroidism. Compound 1 was administered subcutaneously.

[0192] Patients: Adults ages 21 to 60 years.

[0193] Criteria:

[0194] Inclusion Criteria: ^ Healthy men and women (of nonchildbearing potential) between 20 and 60 years of age, inclusive. ^ Body mass index between 20.0 and 32.0 kg / m2, inclusive. ^ No clinically meaningful findings on physical examination, electrocardiogram, laboratory tests or vital signs. ^ Subject has been given signed informed consent.

[0195] Exclusion Criteria: • History of any significant illness or disorder. • Acute illness within 30 days of administration of first dose of study drug. • Positive screening result for HIV, hepatitis B or hepatitis C. • History of or current substance abuse (drug or alcohol) within past 1 year or positive test for drugs of abuse during screening. • Use of nicotine-containing or vaping products within 3 months prior to screening or check-in • Use of cannabis within 45 days prior to check-in. • Donation of blood within 3 months prior to screening, plasma within 2 weeks prior to screening or platelets within 6 weeks prior to screening. • Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within past 30 days.

[0196] Study Design: • This trial was designed to determine the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of Compound 1 vs. placebo in healthy participants (FIG.1).

[0197] Primary Objective: • Evaluate the safety and tolerability of Compound 1 vs. placebo in healthy participants. Secondary Objective: • Evaluate the pharmacokinetic and pharmacodynamic effects of Compound 1 vs. placebo in healthy participants.

[0198] Adverse Events:

[0199] Compound 1 was well tolerated for over four weeks at different doses tested (Table 2). No serious or severe treatment emergent adverse event (TEAE). No symptomatic hypercalcemia. Adverse events that lead to study drug discontinuation were from: 4 COVID-19, and 2 hypercalcemia. The only TEAE occurring in ≥ 3 participants (any cohort) was COVID-19 Table 2:aMost common TEAEs defined in those occurring in ≥ 3 patients in any treatment group. Example 3: PK Assessments

[0158] Compound 1 was subcutaneously injected to the subjects at different doses and blood samples were drawn to complete pharmacokinetic (PK) assessments. PK assessments were calculated using standard methods. PK data was presented in FIG. 2 and the below Table 3. Compound 1 and compound 2 showed linear and dose proportional plasma concentrations.

[0159] Peak to trough was calculated using the ratio between the highest plasma concentration and the lowest plasma concentration of compound 2 at steady state. As shown in FIG. 2, the highest and lowest plasma concentration lead to a peak to trough ratio of the active drug to be about 1.47 to 1.79.

[0160] The half-life of compound 1 and compound 2 were calculated using standard methods and are shown in Table 3. Additionally, FIG. 2 illustrates that the repeat administration of compound 1 leads to accumulation of active drug (compound 2) until steady state is achieved. Table 3

[0200] PD Assessments:

[0201] Compound 1 was subcutaneously injected to the subjects at different doses and blood samples were drawn to complete pharmacodynamic (PD) assessments. C-terminal telopeptide (CTX) biomarker was measured and presented in FIG.3. Procollagen type I N-terminal propeptide (P1NP) biomarker was measured and presented in FIG.4.

[0202] PD assessments also included assessment of changes in albumin-adjusted serum calcium levels and suppression of endogenous PTH secreted by the parathyroid gland (FIG.7). Serum calcium levels were assessed by either the maximal increase in serum calcium (Emax,adj), FIG.6A, or the total serum calcium levels between injections (AUEC0-τ, adj), FIG.6B, in a dose- and time-dependent fashion. Example 4: A Phase 2, Randomized, Double Blind, Placebo Controlled Study of Compound 1 in adult patients with hypoparathyroidism.

[0203] The safety, tolerability and efficacy of three doses of Compound 1 (SEQ ID NO: 1) over a 12-week period is investigated. The primary endpoint of the Phase 2 clinical trial is the proportion of patients who can discontinue active vitamin D and reduce calcium supplements to less than or equal to 1000 mg per day after 12 weeks of treatment while maintaining normal serum calcium levels. Secondary endpoints include safety and tolerability of Compound 1 and characterization of the pharmacokinetics and pharmacodynamic activity (including urine calcium, serum phosphorus, 1,25 dihydroxyvitamin D and bone biomarkers) and the impact on quality of life using patient-reported outcome tools. The primary goal of the Phase 2 clinical trial is to define a Compound 1 dose that is effective, safe and well-tolerated while allowing for a well-ordered withdrawal of active vitamin D and calcium supplements and maintaining a normal serum and urinary calcium level.

[0204] Patients are randomized (1:1:1:1) to weekly subcutaneous injections of placebo and 400 µg, 600 µg, and 800 µg of Compound 1. The 12-week treatment period is comprised of an eight-week fixed dose period and a four-week titration period. During the titration period, patients who have not been able to discontinue active vitamin D and / or reduce calcium supplements may up-titrate the study drug using a protocol-specified algorithm. Patients completing the 12-week treatment period will be eligible to participate in a 104-week long-term extension study.

Claims

CLAIMS WHAT IS CLAIMED IS:

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

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

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

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

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

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

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

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

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

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

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

12. A method of treating a subject with hypoparathyroidism, osteoporosis, or osteopenia, comprising administering to the subject once a week 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 with hypoparathyroidism, osteoporosis, or osteopenia, comprising administering to the subject once a week 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 of claims 13 or 14, wherein the dose is at least about 200 μg.

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

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

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

19. The method of any one of claims 13 to 18, wherein the dose is at most 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 of any one of claims 13 to 28, wherein the method is for treating hypoparathyroidism in a subject in need thereof.

30. The method of any one of claims 13 to 28, wherein the method is for treating osteoporosis, or osteopenia, in a subject in need thereof.

31. A pharmaceutical composition comprising SEQ ID NO: 1 wherein the pharmaceutical composition is suitable for once a week subcutaneous administration, wherein after administration of SEQ ID NO: 1, a pharmacokinetic profile of SEQ ID NO: 2 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 is less than about 1.8 in plasma.

33. The pharmaceutical composition of claims 31 or 32, wherein the peak to trough ratio is less than about 1.6 in plasma.

34. The pharmaceutical composition of any one of claims 31 to 33, wherein the peak to trough ratio is greater than about 1.1 in plasma.

35. The pharmaceutical composition of any one of claims 31 to 34, wherein the peak to trough is ratio greater than about 1.2 in plasma.

36. The pharmaceutical composition of any one of claims 31 to 35, wherein the peak to trough ratio is about 1.4 in plasma.

37. The pharmaceutical composition of any one of claims 31 to 35, wherein the peak to trough ratio is about 1.5 in plasma.

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

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

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

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

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

43. The pharmaceutical composition of any one of claims 31 to 42, wherein the subcutaneous administration occurs with a pen device.

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

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

46. A method of treating a subject with hypoparathyroidism, comprising: (a) determining a level of CTX-1 of the subject upon once a week administration of SEQ ID NO: 1 to the subject, and (b) providing continued once a week administration of SEQ ID NO: 1 to the subject, 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 a dose comprising the SEQ ID NO: 1 is administered to the subject, wherein the dose is less than 1000 μg once a week.

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

50. The method of any one of claims 46 to 49, further comprising (c), administering to the subject a therapeutically effective amount of an anti-resorptive medication.

51. A method of treating a subject with hypoparathyroidism, comprising: (a) determining a level of Procollagen type I N-terminal propeptide (P1NP) of the subject upon weekly administration of SEQ ID NO: 1 to the subject, and (b) providing continued once a week administration of SEQ ID NO: 1 to the subject, wherein the level of P1NP is greater than about -50 μg / L in the subject.

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

53. The method of claims 51 or 52, wherein determining further comprises obtaining a biological sample from the subject and measuring the level of P1NP in the sample from the subject.

54. The method of claim 53, further comprising (c), administering to the subject a therapeutically effective amount of an anti-resorptive medication.

55. A pharmaceutical composition comprising SEQ ID NO: 1, wherein the pharmaceutical composition is suitable for subcutaneous administration once a week, wherein SEQ ID NO: 2 has a maximum plasma concentration (Cmax) of at most about 6 (nmol / L), when a dose comprising the SEQ ID NO: 1 is administered to the subject, wherein the dose is between 200 μg to 900 μg.

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

57. The pharmaceutical composition of claim 55 or 56, wherein the maximum plasma concentration (Cmax) of SEQ ID NO: 2 is at most about 5 (nmol / L).

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

59. The pharmaceutical composition of any one of claims 55 to 58, wherein SEQ ID NO: 1 has a maximum plasma concentration (Cmax) of at most about 20 (nmol / L).

60. The pharmaceutical composition of any one of claims 55 to 59, wherein SEQ ID NO: 1 has a maximum plasma concentration (Cmax) of at least about 3 (nmol / L).

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

62. The pharmaceutical composition of any one of claims 55 to 61, wherein the ratio of Cmax 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 a week, wherein SEQ ID NO: 2 has a half-life of 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 of claims 63 or 64, wherein the release half-life is greater than about 140 hours.

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