Parathyroid hormone compounds in treatment of hypoparathyroidism

Abstract

To provide a method for management and / or treatment of hypoparathyroidism (HP) in a subject.SOLUTION: A method comprises the step for administering a dose of a circulating parathyroid hormone (PTH) compound having a specific amino acid sequence to a subject, where administration of the PTH compound maintains or improves bone integrity.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the use of parathyroid hormone compounds in the treatment of hypoparathyroidism. [Background technology]

[0002] Hypoparathyroidism (HP) is a rare disease characterized by absent or inappropriately low concentrations of circulating parathyroid hormone (PTH), leading to hypocalcemia, hyperphosphatemia, and elevated fractional excretion of calcium (FECa) in the urine, or hypercalciuria.

[0003] The physiological role of PTH is to maintain a homeostatic balance of serum calcium, which plays a key role in several biological processes. In this tightly regulated process, low serum calcium is sensed by calcium-sensing receptors in parathyroid cells, which in turn stimulates the parathyroid gland to release PTH into the circulation. Signaling is modulated by the PTH receptor at multiple distinct sites, resulting in increased absorption of dietary calcium in the intestine (i.e., by converting 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D), increased reabsorption of calcium into the blood prior to excretion by the kidney, and release of calcium from mineral-rich deposits in the bone matrix (Ref. 1).

[0004] The clinical symptoms of HP reflect effects on numerous tissues and organ systems, including muscles, brain, heart, and kidneys, and range from mild disease with paresthesia (burning or tingling) and muscle spasms to severe symptoms such as laryngospasm and seizures (Reference 2). In HP, bone turnover is reduced, accompanied by a reduction in biological markers of bone resorption and formation. Reduced bone turnover in HP results in increased mean bone mineral density compared with age- and sex-matched controls, but results in a wide range of abnormal bone structure due to the accumulation of damaged or overly mature bone (Reference 3). Increased bone density and reduced bone quality appear to create a balance, such that the risk of fracture in HP patients appears to be similar to that of normal subjects in population studies (References 13, 14), but it is logical to assume that treatments that reduce bone density in HP patients may increase the risk of fracture due to poor bone structure. Recent studies have indeed demonstrated that morphologically, vertebral fractures are increased in patients with hypoparathyroidism compared with matched healthy subjects (Refs. 15, 16).

[0005] Approximately 80% of the approximately 80,000 HP patients in the United States and 110,000 in the European Union are women. Despite available treatments, patients experience persistent life-altering symptoms and often develop complications and comorbidities that reduce their quality of life (QoL), creating a patient population with specific clinical needs. Approximately 17% of patients with hypoparathyroidism have osteopenia or osteoporosis, and 53% are peri- or postmenopausal women who are at increased risk of developing osteoporosis. For these patients, any bone loss is detrimental. In addition, approximately half of these patients have hypercalciuria, which contributes to the development of nephrocalcinosis, kidney stones, and progressive renal disease. As a result, approximately 26% of patients with hypoparathyroidism have chronic kidney disease or chronic renal failure, highlighting the importance of reducing urinary calcium excretion as an important treatment goal.

[0006] The primary goals in the treatment and management of patients with HP are: i) to maintain stable serum calcium concentrations at normal levels for 24 hours, thereby ameliorating or preventing signs and symptoms of HP for 24 hours; ii) to normalize urinary calcium excretion, or elevated levels of calcium in the urine, in patients with hypercalciuria to avoid associated impairment of renal function, nephrocalcinosis, and chronic kidney disease; and iii) to preserve bone integrity and mass to prevent an increased risk of fracture in patients.

[0007] Conventional therapy for HP patients includes calcium supplements and activated vitamin D. These supplements only control serum calcium short-term and do not adequately control symptoms. As a result, HP patients often need to take significant amounts of supplements throughout the day (10-15 tablets or more per day) to adequately control serum calcium levels. In addition, calcium / vitamin D supplementation does not improve insufficient renal reabsorption of calcium in HP patients and, when used chronically, exacerbates potential deleterious effects on the kidney. The continued excretion of calcium from the kidneys by calcium supplementation is toxic to tissues and greatly increases the chances of chronic kidney disease, kidney stones, and kidney dysfunction. This is exacerbated by an increased risk of kidney stones resulting in kidney injury due to infection and obstruction of urine outflow.

[0008] Natpara™ is a recombinant natural human PTH ((rh)PTH(1-84)) approved by the FDA and EMA as an adjunct treatment to calcium and vitamin D supplements to control hypocalcemia in HP patients. However, the drug has a short half-life and is unable to control calcium levels throughout the day. Clinical trials have not demonstrated a reduction in urinary calcium excretion or an improvement in quality of life (References 5, 6). Although short-term exposure to intermittent administration of PTH has been shown to increase bone mass, clinical trials with (rh)PTH(1-84) have shown a failure to control serum calcium for 24 hours and the presence of adverse effects such as elevated urinary calcium excretion and hyper / hypocalcemia and vasoactive events in many subjects (Reference 5).

[0009] To overcome the limitations of Natpara™, sustained, long-exposure PTH formulations have been developed. One of these, TransCon™ PTH, is a sustained-release injectable prodrug formulation of native PTH(1-34) that provides stable serum calcium levels and may improve symptom control in some diseases, as well as promote renal reabsorption of calcium in patients, thereby potentially reducing the risk of kidney disease. TransCon™ PTH is currently in late-stage clinical development by Ascendis Pharma A / S.

[0010] However, continuous, non-pulsatile administration of PTH has been observed to induce safety issues in animal models and clinical trials, most notably bone resorption, which raises concerns for HP patients, most of whom are peri- or postmenopausal women already at increased risk for osteoporosis (Refs. 17, 18, 19).

[0011] Treatment of TPTX rats with TransCon™ PTH was shown to produce a continuous non-pulsatile infusion-like pharmacokinetic profile, with a significant reduction in bone mineral density (BMD) observed compared to both sham-operated and TPTX rats treated with vehicle alone (Reference 10). When assessing bone mineral density, a reduction in the mean T-score was observed over 52 weeks of treatment in human HP patients with TransCon™ PTH (Reference 12 and Ascendis' webpage https: / / ascendispharma.gcs-web.com / , July 2023, incorporated herein by reference).

[0012] TransCon™ PTH has been shown to reduce mean 24-hour urinary calcium levels in HP patients, however data from a Phase 3 trial indicate that many patients remain hypercalciuric after 6 months of treatment (Ref. 11, Figure 7).

[0013] In conclusion, there remains an unmet need for a treatment for hypoparathyroidism that can maintain consistent normal blood calcium levels, restore normal renal calcium resorption in hypercalciuric patients, and preserve bone integrity and mass. No treatment for HP currently available or in clinical development has demonstrated comprehensive therapeutic efficacy across all of these therapeutic goals. Summary of the Invention

[0014] The object of the present invention is to remedy at least some of the problems existing in the prior art.

[0015] According to one embodiment, the present invention relates to a method for the management and / or treatment of hypoparathyroidism (HP) in a subject, the method comprising administering to the subject a dose of a PTH compound, wherein the PTH compound has an amino acid sequence as set forth in SEQ ID NO: 10, and wherein administration of the PTH compound maintains or improves bone integrity.

[0016] According to one embodiment, the present invention relates to a method for normalizing urinary calcium levels in a hypercalciuric subject suffering from hypoparathyroidism, the method comprising administering to the subject a dose of a PTH compound, wherein the PTH compound has the amino acid sequence set forth in SEQ ID NO:10.

[0017] According to one embodiment, the present invention relates to a method for maintaining steady state blood calcium levels in a subject suffering from hypoparathyroidism, the method comprising administering to the subject a dose of a PTH compound, wherein the PTH compound has the amino acid sequence set forth in SEQ ID NO:10.

[0018] According to one embodiment, the present invention relates to a method for managing or maintaining hypoparathyroidism in a subject, the method comprising the steps of i) administering to the subject a dose of a PTH compound, the PTH compound having an amino acid sequence as set forth in SEQ ID NO: 10, and ii) tapering a standard treatment for hypoparathyroidism in the subject.

[0019] According to one embodiment, the present invention relates to a method for restoring bone turnover in a subject with hypoparathyroidism, the method comprising administering to the subject a dose of a PTH compound, wherein the PTH compound has the amino acid sequence shown in SEQ ID NO:10.

[0020] According to one embodiment, the present invention relates to a method for managing or treating hypoparathyroidism in a subject, the method i) maintaining serum calcium levels within the normal range without the need for oral calcium and active vitamin D supplements, ii) normalizing 24-hour urinary calcium, and iii) maintaining bone integrity, the method comprising administering to the subject a dose of a PTH compound, wherein the PTH compound has the amino acid sequence set forth in SEQ ID NO:10.

[0021] According to one embodiment, the present invention relates to a method for managing or treating hypoparathyroidism in a population of subjects, the method i) maintaining serum calcium levels within the normal range without the need for oral calcium and active vitamin D supplementation, ii) normalizing 24-hour urinary calcium, and iii) maintaining bone integrity, the method comprising administering to subjects in the population of subjects a dose of a PTH compound, wherein the PTH compound has the amino acid sequence set forth in SEQ ID NO:10.

[0022] According to one embodiment, the present invention relates to a pharmaceutical composition comprising a dose of a PTH compound having an amino acid sequence as set forth in SEQ ID NO: 10, the dose being between 10 μg / day and 120 μg / day. In some examples, the pharmaceutical composition comprises a dose of a PTH compound between 20 μg / day and 120 μg / day.

[0023] Additional and / or alternative features, aspects, and advantages of the practice of the invention will become apparent from the following description, the accompanying drawings, and the appended claims.

[0024] For a better understanding of the present invention, together with other aspects and further features thereof, reference is made to the following description, which should be used in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 is a graph showing serum calcium levels over time in a parathyroidectomy (PTX) mouse model following administration of the indicated doses of AZP-3601 and PTH(1-34). [Diagram 2] 1 is a graph showing serum calcium levels in a thyroid-parathyroidectomized (TPTX) rat model administered the indicated doses of AZP-3601 over a 28 day period. [Diagram 3] FIG. 1 is a graph showing urinary calcium levels in a PTX mouse model following administration of the indicated doses of AZP-3601. [Figure 4]FIG. 1 is a graph showing urinary calcium levels in a TPTX rat model treated with repeated doses of AZP-3601. [Diagram 5] 1 is a graph showing serum calcium levels in non-human primates up to 96 hours following administration of the indicated doses of AZP-3601, PTH(1-84), and PTH(1-34). [Figure 6] Figures 6A, 6B, and 6C are graphs showing a direct comparison of the distal femur in TPTX rats after 14 days of treatment with either daily PTH(1-34) injections at doses that normalized serum calcium (Figure 6A), continuous PTH(1-34) infusion (Figure 6B), or daily AZP-3601 injections (Figure 6C). [Figure 7] 1 is a graph showing the effect of daily administration of AZP-3601 on bone mineral content in TPTX rats. [Figure 8] Figures 8A, 8B, 8C and 8D are graphs showing that daily treatment of healthy non-human primates with AZP-3601 has no significant effect on either anabolic or catabolic bone biomarkers. Figures 8A (male) and 8B (female) show the evolution of the catabolic bone biomarker CTX over 39 weeks of daily AZP-3601 administration. Figures 8C (male) and 8D (female) show the evolution of the anabolic bone biomarker P1NP over 39 weeks of daily AZP-3601 administration. [Figure 9] Figures 9A, 9B, 9C, 9D, 9E, and 9F are graphs showing bone mineral density (BMD) by quantitative computed tomography (qCT) after 39 weeks of treatment with the indicated doses of AZP-360 in non-human primates. Figure 9A shows femur BMD in males, Figure 9B shows femur BMD in females, Figure 9C shows tibia BMD in males, Figure 9D shows tibia BMD in females, Figure 9E shows L4 BMD in males, and Figure 9F shows L4 BMD in females. [Figure 10]FIG. 1 is a graph showing that administration of AZP-3601 to normal healthy subjects over 14 days causes a dose-dependent and sustained steady-state increase in serum calcium levels (multiple ascending dose cohorts: 5 cohorts / n=8-10 per cohort). [Figure 11] Figures 11A and 11B are graphs showing the effect of administration of AZP-3601, which can eliminate the need for calcitriol supplementation. Figure 11A shows the reduction in calcitriol over 84 days of administration of AZP-3601 (using a starting dose of 20 μg / day) in C1 hypoparathyroidism patients whose expansion period has been completed, N=10. Figure 11B shows the reduction in calcitriol over 84 days of administration of AZP-3601 (using a starting dose of 10 μg / day) in C2 hypoparathyroidism patients whose expansion period has been completed, N=14. [Figure 12] Figures 12A and 12B are graphs showing the possibility of administering AZP-3601 to eliminate oral calcium intake as part of standard treatment. Figure 12A shows the reduction in oral calcium intake (mg / day) over 84 days of administering AZP-3601 (using a starting dose of 20 μg / day) in C1 hypoparathyroidism patients who have completed the extended period, N=10. Figure 12B shows the reduction in oral calcium intake (mg / day) over 84 days of administering AZP-3601 (using a starting dose of 10 μg / day) in C2 hypoparathyroidism patients who have completed the extended period, N=14. [Figure 13] Figures 13A and 13B are graphs showing that administration of AZP-3601 maintains mean serum calcium within the target range. Figure 13A shows the maintained mean serum calcium levels over 84 days of administration of AZP-3601 (using a starting dose of 20 μg / day) in C1 hypoparathyroidism patients whose expansion period has been completed, N=10. Figure 13B shows the maintained mean serum calcium levels over 84 days of administration of AZP-3601 (using a starting dose of 10 μg / day) in C2 hypoparathyroidism patients whose expansion period has been completed, N=10. [Figure 14]Figures 14A and 14B are graphs showing that administration of AZP-3601 induces a rapid, widespread and sustained reduction and normalization of mean 24-hour urinary calcium. Figure 14A shows the evolution of 24-hour μCa (mg / 24 hours) over 84 days of administration of AZP-3601 in C1 hypoparathyroidism patients whose extended period has ended, N=10. Figure 14B shows the evolution of 24-hour μCa (mg / 24 hours) over 84 days of administration of AZP-3601 in C2 hypoparathyroidism patients whose extended period has ended, N=14. [Figure 15] Figures 15A and 15B are graphs showing that administration of AZP-3601 induces rapid and widespread reduction and sustained normalization of mean 24-hour urinary calcium in hypoparathyroid subjects with hypercalciuria at baseline. Figure 15A shows the evolution of 24-hour μCa (mg / 24 hours) over 84 days of AZP-3601 administration in C1 hypoparathyroid patients whose extended period has ended, N=7. Figure 15B shows the evolution of 24-hour μCa (mg / 24 hours) over 84 days of AZP-3601 administration in C2 hypoparathyroid patients whose extended period has ended, N=7. [Figure 16] Figures 16A-16D are graphs showing that treatment with AZP-3601 induces a progressive increase in both anabolic and catabolic bone biomarkers to median normal levels from 4 to 8 weeks. Figure 16A shows the evolution of the catabolic bone biomarker CTx over 84 days of AZP-3601 administration in C1 hypoparathyroid patients whose expansion period has been completed, N=10. Figure 16B shows the evolution of the anabolic bone biomarker P1NP over 84 days of AZP-3601 administration in C1 hypoparathyroid patients whose expansion period has been completed, N=10. Figure 16C shows the evolution of the catabolic bone biomarker CTx over 84 days of AZP-3601 administration in C2 hypoparathyroid patients whose expansion period has been completed, N=14. Figure 16D shows the evolution of the anabolic bone biomarker P1NP over 84 days of AZP-3601 administration in C2 hypoparathyroid patients whose expansion period has been completed, N=14. [Figure 17]Figures 17A and 17B are graphs showing that bone mineral density and trabecular bone score remain stable upon administration of AZP-3601. Figure 17A shows that bone mineral density (BMD) remains stable in hypoparathyroid subjects administered AZP-3601 over 84 days of treatment. Figure 17B shows that trabecular bone score (TBS) remains stable in hypoparathyroid subjects administered AZP-3601 over 84 days of treatment. [Figure 18] Figures 18A and 18B are graphs showing the effect of AZP-3601 administration on Z-score a, d and T-score bone. Figure 18A shows the Z-score that compares the BMD measured in patients with that of age- and sex-matched healthy subjects. Figure 18B shows the T-score that compares the BMD measured in patients with that of young healthy subjects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or carried out in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0027] The use of "including," "comprising," "having," "containing," "involving," and variations thereof herein is meant to encompass not only the items listed below, but also, optionally, additional items. In the following description, like reference numbers refer to like elements.

[0028] As used herein, the phrase "standard of care" or "SOC" refers to oral administration of calcium and active vitamin D.

[0029] As used herein, the phrase "tapering standard of care" refers to reducing and / or eliminating the administration of oral calcium and active vitamin D.

[0030] As used herein, the term "normal calcium level" refers to a serum calcium level of 8.3 mg / dL to 10.6 mg / dL or 2.075 mmol / L to 2.65 mmol / L. In humans, the normal level in certain instances corresponds to a serum calcium level (albumin adjusted) above 8.5 mg / dL.

[0031] The phrase "albumin-adjusted calcium level" means that the measured serum calcium level is corrected for calcium bound to albumin according to the following formula: Albumin-adjusted serum calcium (mg / dL) = Measured total Ca (mg / dL) + 0.8 × (4.0 - serum albumin [g / dL]).

[0032] As used herein, the phrase "normal urinary calcium level" refers to a urinary calcium level of 100-300 milligrams per day (mg / day) or 2.50-7.50 millimoles per 24 hours (mmol / 24 hours). For a diet low in calcium, the amount of calcium in the urine would be 50-150 mg / day or 1.25-3.75 mmol / 24 hours.

[0033] As used herein, the term "hypercalciuria" refers to excess calcium in the urine. It may be secondary, i.e., a side effect of some other conditions (e.g., HP) that cause high levels of calcium in the bloodstream, or it may be "idiopathic," occurring on its own with normal blood calcium levels. Typically, hypercalciuria refers to urinary calcium levels greater than 250 mg / 24 hours in women and greater than 300 mg / 24 hours in men.

[0034] As used herein, the expression "bone mineral density (BMD)" refers to the amount of bone mineral in bone tissue. The concept is the mass of mineral per volume of bone (related to density in the physical sense). Measurement of bone mineral density is used in clinical situations as an indirect indicator of osteoporosis and risk of fracture. It is measured by a procedure called densitometry. The T-score is the relevant measurement when screening for osteoporosis. It is the amount of bone mineral at that site compared to the "young normal reference mean". It is a comparison of the bone mineral content of the subject to that of a healthy 30-year-old. Normal is a T-score of -1.0 or higher. Osteopenia is defined as -1.0 to -2.5. Osteoporosis is defined as -2.5 or lower, meaning a bone mineral density that is two and one-half standard deviations below the mean for a 30-year-old man / woman. The Z-score for bone mineral density is a comparison to the "normal value for age" and is usually used in cases of severe osteoporosis. There is a statistical association between poor bone mineral density and a higher probability of fracture. Foot and pelvic fractures resulting from falls are a significant public health problem, especially in elderly women, resulting in significant medical costs, inability to live independently, and even risk of death. Bone mineral density measurements are used to screen people for risk of osteoporosis and to identify those who would benefit from measures to improve bone strength.

[0035] The term "parathyroid hormone compound" or "PTH compound" as used herein refers to PTH polypeptides, as well as variants, analogs, orthologs, homologs, derivatives and fragments thereof. The term "PTH compound" also refers to PTH-related polypeptides (PTHrP), such as those identified in Table 1 below, that bind to and activate the common PTH / PTHrPl receptor. Other PTH compounds are discussed in U.S. Patent No. 9,492,508, the contents of which are incorporated herein by reference.

[0036] [Table 1]

[0037] The expression "PTH compound" as used herein also includes poly(amino acid) conjugates having the sequence described above, but with a backbone such as depsipeptide, which includes both amide and non-amide linkages such as ester linkages. Depsipeptide is a chain of amino acid residues whose backbone includes both amide (peptide) and ester linkages. Thus, the term "side chain" as used herein refers to either the moiety attached to the alpha-carbon of the amino acid moiety when the amino acid moiety is connected through an amine bond, such as in proteins and peptides, or the moiety that includes any carbon atom attached to the backbone of the poly(amino acid) conjugate, such as in the case of depsipeptide.

[0038] The term "peptide" as used herein refers to a chain of at least 2 and up to 50 amino acid monomer moieties, which may also be referred to as "amino acid residues" linked by peptide (amide) linkages. The amino acid monomers may be selected from the group consisting of proteinogenic and non-proteinogenic amino acids and may be D- or L-amino acids. The term "peptide" also includes peptidomimetics, such as peptoids, beta-peptides, cyclic peptides and depsipeptides, and encompasses such peptidomimetic chains having up to 50 monomer moieties.

[0039] In one embodiment, the PTH compounds of the present invention have a short circulating half-life but bind to the R of the PTH1 receptor. 0 It is a synthetic 36 amino acid hybrid peptide analogue of human PTH and PTHrP that is designed to bind tightly to the distinct PTH1 receptor conformation R 0The high affinity of the PTH compounds of the present invention for maintains ligand binding through multiple rounds of G protein coupling and activation resulting in greatly extended signal transduction and cellular response (i.e. extended duration of action on calcium metabolism).The short circulating half-life is intended to reduce the possibility of extended PTH receptor exposure that would promote adverse effects on bone (i.e. bone resorption) and contribute to cardiovascular safety events such as orthostatic hypotension.

[0040] In certain embodiments, the PTH compound of the invention is a peptide having the amino acid sequence shown in SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0041] In certain embodiments, the PTH compound of the invention is a peptide having the amino acid sequence set forth in SEQ ID NO:10, also referred to herein as "AZP-3601."

[0042] Pharmacological effects of AZP-3601 have been observed in rodent models of HP and in normal monkeys. In hypoparathyroid mice, a single subcutaneous (sc) injection of AZP-3601 at doses ranging from 10 nmol / kg to 20 nmol / kg increased serum calcium to normal levels for up to 72 hours and reduced serum inorganic phosphorus to normal levels for >8 hours, whereas PTH(1-34) injected at higher doses increased serum calcium and reduced serum inorganic phosphorus in a more transient manner (<8 hours for serum calcium and <4 hours for serum inorganic phosphorus) (ref. 7). Similar results were observed in hypoparathyroid / hypothyroid rats, where we demonstrated that chronic treatment with AZP-3601 for 28 hours restored serum calcium and serum inorganic phosphorus without increasing urinary calcium excretion (ref. 8).

[0043] Administration of AZP-3601 in non-human primates shows that significant maximal effects were measured 24 hours after injection of 2.1 μg / kg to 4.3 μg / kg AZP-3601. The highest dose levels of 10.7 μg / kg or 42.7 μg / kg significantly induced hypercalcemia, with serum calcium remaining elevated for at least 4 days after injection. (8)

[0044] The present invention arises from our unexpected finding that daily administration of a PTH compound, particularly a long-acting PTH compound such as AZP-3601, restores serum calcium levels to normal levels (8.3-10.6 mg / dL or 2.075-2.62 mmol / L) within just 28 days of initiating PTH therapy, allowing for weaning of SOC. Surprisingly, we found that these results were achieved without compromising bone integrity, i.e., without a reduction in bone mass. We also unexpectedly found that daily administration of AZP-3601 normalizes urinary calcium in hypercalciuric subjects. Another unexpected aspect of this finding arises from our observation that the sustained effect was achieved despite the short circulating half-life of AZP-3601.

[0045] Thus, we found that daily administration of AZP-3601 produced a neutral effect on bone in subjects with already balanced bone turnover as a preclinical rodent model of acutely parathyroidectomized HP. In addition, we demonstrated that the balanced anabolic / catabolic effects of daily AZP-3601 produced a balanced physiological anabolic / catabolic effect on bone in human subjects with established HP and slowed / arrested bone turnover.

[0046] In one embodiment, the present invention therefore relates to a method for the management and / or treatment of hypoparathyroidism (HP) in a subject, the method comprising administering to the subject a dose of a PTH compound as defined herein.

[0047] In some cases, the subject in need of the method of the present invention is a hypoparathyroidism patient (HP patient). Hypoparathyroidism can lead to hypocalcemia and hyperphosphatemia. As a result, hypoparathyroidism patients can experience a range of severe and potentially life-threatening short-term and long-term complications, including neuromuscular irritability, renal complications, and vascular calcification. Cognitive impairment is also common. Without regulation of PTH in HP patients, there is a state of low bone turnover, and bone turnover markers are lower than half of the normal range. As a result, HP patients have slightly higher bone mineral density compared to healthy individuals. HP patients have slightly higher average BMD compared to healthy individuals. However, although the average value for BMD is higher than subjects without HP, there is considerable diversity in the HP population, and many patients have lower than average BMD. Many of these patients are postmenopausal women, and may have developed osteopenia or osteoporosis several years before the onset of HP. Furthermore, despite the increased bone density observed in some patients, abnormal bone microarchitecture in HP patients may lead to reduced resilience. The increase in bone mineral density observed in HP patients does not increase the protective effect against fracture risk as demonstrated in population studies, but may be due to a countervailing effect of the decreased bone quality associated with the disease. There is one subset of HP patients who are particularly prone to hypercalciuria: those with autosomal dominant hypoparathyroidism (5, 6, 8, 9). This is because, at baseline before treatment, constitutively active calcium receptors in the kidney activate renal calcium excretion.

[0048] In some instances, the PTH compound is administered to the subject daily. In some instances, the PTH compound is administered to the subject once a day.

[0049] In some embodiments, the subject who needs to administer PTH compounds according to the method of the present invention includes a subject who is at risk of or has experienced increased bone loss.In some embodiments, the subject who needs to administer PTH compounds according to the method of the present invention includes a subject who is at risk of or has experienced decreased bone integrity.In some examples, the subject who needs to administer PTH compounds according to the present invention is a hypercalciuric subject (i.e., demonstrates excess calcium in urine).In some embodiments, the subject who needs to administer PTH compounds according to the method of the present invention is at risk of or has experienced increased bone loss, including a subject who is hypercalciuric.In some examples, the subject who needs to administer PTH compounds according to the method of the present invention is a perimenopausal or postmenopausal woman.In some other examples, the subject suffers from bone loss-related conditions, such as osteopenia and osteoporosis.

[0050] In one embodiment, the method of the invention further comprises tapering a standard of care treatment for HP in the subject while administering a PTH compound to the subject.

[0051] In some embodiments, tapering the subject off standard of care is performed by decreasing daily intake of oral calcium and decreasing daily intake of active vitamin D. In some other implementations, tapering the subject off standard of care is performed until administration of a daily dose of the PTH compound results in a stable albumin-corrected serum calcium level in the subject.

[0052] In some embodiments, tapering a subject's standard of care is done in a stepwise manner until administration of vitamin D is eliminated and administration of calcium is reduced or reduced to below 600 mg / day.

[0053] In some embodiments, the method of the present invention comprises tapering the standard treatment in the subject within 12 weeks from when the first dose of PTH compound is administered. In some embodiments, the method of the present invention comprises tapering the standard treatment in the subject within 10 weeks from when the first dose of PTH compound is administered. The method of the present invention comprises tapering the standard treatment in the subject within 8 weeks from when the first dose of PTH compound is administered. The method of the present invention comprises tapering the standard treatment in the subject within 6 weeks from when the first dose of PTH compound is administered. The method of the present invention comprises tapering the standard treatment in the subject within 4 weeks from when the first dose of PTH compound is administered. The method of the present invention comprises tapering the standard treatment in the subject within 2 weeks from when the first dose of PTH compound is administered. Various titration schemes are suitable. In certain embodiments, tapering the standard treatment in the patient comprises a stepwise reduction, followed by a complete omission of orally administered active vitamin D, followed by a stepwise reduction, followed by a complete omission of orally administered calcium. It is understood that some subjects' diet does not allow sufficient calcium nutritional intake (usually considered to be <750mg calcium per day), for example, as may be the case for lactose-tolerant subjects.These subjects continue to take oral calcium supplementation, for example, in the form of calcium oral administration once a day, such as in the form of calcium tablets.However, this calcium supplementation is not related to the treatment of hypoparathyroidism, and is also a common practice in healthy subjects.

[0054] In some embodiments, the daily dose of the PTH compound administered to the subject ranges from 10 μg / day to 120 μg / day, or from 10 μg / day to 100 μg / day, or from 10 μg / day to 90 μg / day, or from 10 μg / day to 80 μg / day daily, or from 10 μg / day to 70 μg / day, or from 10 μg / day to 60 μg / day, or from 10 μg / day to 50 μg / day, or from 20 μg / day to 120 μg / day, or from 20 μg / day to 100 μg / day, or from 20 μg / day to 90 μg / day, or from 20 μg / day to 80 μg / day daily, or from 20 μg / day to 70 μg / day, or from 20 μg / day to 60 μg / day, or from 20 μg / day to 50 μg / day.

[0055] In some embodiments, the daily dose of the PTH compound administered to the subject is 120 μg / day. In some embodiments, the daily dose of the PTH compound administered to the subject is 100 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 90 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 80 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 70 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 60 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 50 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 40 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 30 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 20 μg / day. In some other embodiments, the daily dose of the PTH compound administered to the subject is 10 μg / day.

[0056] In some embodiments, the method of the present invention is a stepwise method, in which an initial daily dose of PTH is administered to the subject on the first day of treatment. On subsequent days of treatment, the subject tapers off standard treatment by decreasing the intake of active vitamin D and calcium until the intake of active vitamin D is no longer required and calcium intake is reduced to 500 mg / day or less.

[0057] In some instances, the reduction in oral intake of active vitamin D is as follows: first, a 50% reduction from the baseline dose of oral active vitamin D; second, a 75% reduction from the baseline dose of oral active vitamin D; and a 100% reduction from the baseline dose of oral active vitamin D.

[0058] In some instances, the reduction in oral calcium intake is as follows: first, a 50% reduction from the baseline dose of calcium; second, a 75% reduction from the baseline dose of calcium; and remaining at only 600 mg / day or less of calcium intake.

[0059] In some embodiments, the method also includes increasing the initial daily dose of PTH to achieve the desired reduction in calcium and active vitamin D intake.In some examples, the initial daily dose of PTH compound is 5 μg / day, 10 μg / day, 15 μg / day, 20 μg / day, 25 μg / day, 30 μg / day, 35 μg / day, 40 μg / day, 45 μg / day, 50 μg / day, 55 μg / day, 60 μg / day, 65 μg / day, 70 μg / day, 75 μg / day, 80 μg / day, 85 μg / day, 90 μg / day, 95 μg / day, 100 μg / day, 110 μg / day, or 120 μg / day. In some cases, the daily dose of the administered PTH compound is increased to 2 μg / day, 5 μg / day, 10 μg / day, 15 μg / day, 20 μg / day, 25 μg / day, 30 μg / day, or more. The increase in the PTH compound may be required several days or weeks after administration of the initial dose of the PTH compound.

[0060] In some embodiments, the method of the invention includes initiating treatment with administration of an initial daily dose of a PTH compound as defined herein at a concentration of 10 μg / day to a subject as a subcutaneous (sc) injection, and simultaneously reducing the administration of active vitamin D by at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, or at least 50%. The method also includes monitoring serum calcium (and albumin) concentrations every 3-7 days after initiation of treatment (e.g., after administration of the initial dose of the PTH compound) and after each dose change. The dose of the PTH compound may be titrated daily, every few days, weekly, every 2 weeks, 3 weeks, or every 4 weeks, with the goal of, for example, discontinuing active vitamin D and reducing oral calcium supplementation to amounts as low as 500 mg / day while keeping serum calcium within the low normal range. After the initial titration phase when a stable regimen is achieved, serum calcium and phosphate may be monitored every 3-6 months, and urinary calcium excretion may be monitored annually.

[0061] In another embodiment, the present invention relates to a method for managing or treating hypoparathyroidism in a subject, wherein an initial dose of PTH compound is administered to the subject in a dosage regimen, and the initial dose of PTH compound is increased during the course of treatment, and the dosage regimen includes: i) titrating the initial dose of PTH compound administered to the subject to produce normal serum calcium levels in the subject and maintaining the subject at such initial dose for a first period of time; ii) increasing the initial dose of PTH compound administered to the subject for a second period immediately following the first period of time to achieve a second dose; and iii) optionally increasing the second dose of PTH compound for a third or further period of time to achieve a third dose. In some cases, the third or further dose is different from the second dose or the initial dose by 2 μg / day, 5 μg / day, 10 μg / day, 15 μg / day, 20 μg / day, 25 μg / day, 30 μg / day or more. In some cases, the second dose is different from the first dose by 2 μg / day, 5 μg / day, 10 μg / day, 15 μg / day, 20 μg / day, 25 μg / day, 30 μg / day or more.In certain embodiments, the first period is at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.In certain embodiments, the second period is at least 1 month, at least 2 months, at least 3 months, or at least 4 months.

[0062] In another embodiment, the present invention relates to a method for managing or treating hypoparathyroidism in a subject, which allows the subject to i) maintain serum calcium levels within the normal range without the need for oral calcium and active vitamin D supplementation, ii) normalize 24-hour urinary calcium, and iii) maintain bone integrity. The method includes administering to the subject a dose of a PTH compound, wherein the PTH compound has an amino acid sequence as set forth in SEQ ID NO: 10. In some examples, the method allows the serum calcium level to be maintained between 8.3 mg / dL and 10.6 mg / dL or between 2.075 mmol / L and 2.65 mmol / L. In some instances, the method allows for normalization of 24 hour urinary calcium to about 100 mg / day to about 300 mg / day, or about 100 mg / day to about 250 mg / day, or about 100 mg / day to about 200 mg / day, or about 100 mg / day to about 150 mg / day, or about 100 mg / day to about 125 mg / day. In some instances, the method normalizes 24 hour urinary calcium in a subject within 12 weeks of administration of the PTH compound. In some examples, the method allows for normalization of 24-hour urinary calcium to about 100 mg / day to about 300 mg / day within 12 weeks of administration of the PTH compound, or about 100 mg / day to about 250 mg / day within 12 weeks of administration of the PTH compound, or about 100 mg / day to about 200 mg / day within 12 weeks of administration of the PTH compound, or about 100 mg / day to about 150 mg / day within 12 weeks of administration of the PTH compound, or about 100 mg / day to about 125 mg / day within 12 weeks of administration of the PTH compound. In some examples, the subject is a hypercalciuric patient.

[0063] In some cases, the method allows bone biomarkers and bone integrity to be maintained within normal range, thereby restoring bone turnover in HP patients.As used herein, the term "bone turnover" refers to the lifelong process of removing mature bone tissue from the skeleton and forming new bone tissue.These processes also control bone remodeling and replacement after micro-injury as well as after injury such as fracture.

[0064] In some embodiments, the present invention relates to a method for managing or treating hypoparathyroidism in a population of subjects, which allows the subjects of the population to i) maintain serum calcium levels within the normal range without the need for oral calcium and active vitamin D supplementation, ii) normalize 24-hour urinary calcium, and iii) maintain bone integrity. The method includes administering a dose of a PTH compound to the subject, wherein the PTH compound has an amino acid sequence as set forth in SEQ ID NO: 10. In some examples, the method allows at least about 90% of the hypercalciuric subjects of the population to normalize 24-hour urinary calcium. In some examples, the method allows at least about 85% of the hypercalciuric subjects of the population to normalize 24-hour urinary calcium. In some examples, the method allows at least about 80% of the hypercalciuric subjects of the population to normalize 24-hour urinary calcium. In some examples, the method allows at least about 75% of the hypercalciuric subjects of the population to normalize 24-hour urinary calcium. In some examples, the method allows for normalization of 24-hour urinary calcium in at least about 70% of the hypercalciuric subjects of a population. In some examples, the method allows for normalization of 24-hour urinary calcium in at least about 65% of the hypercalciuric subjects of a population. In some examples, the method allows for normalization of 24-hour urinary calcium in at least about 60% of the hypercalciuric subjects of a population. In some examples, the method allows for normalization of 24-hour urinary calcium in at least about 55% of the hypercalciuric subjects of a population. In some examples, the method allows for normalization of 24-hour urinary calcium in at least about 50% of the hypercalciuric subjects of a population.

[0065] In certain embodiments, administration of the PTH compound is oral, intravenous, intramuscular, ocular, topical, cutaneous, subcutaneous, or rectal.

[0066] In certain embodiments, the method of the present invention comprises administering PTH compound by injection.In certain examples, PTH compound is administered by subcutaneous injection.In certain examples, PTH compound is administered by subcutaneous injection once a day.

[0067] In some embodiments, the present invention relates to a pharmaceutical composition for managing or treating hypoparathyroidism in a subject, the pharmaceutical composition comprising a daily dose of a PTH compound.In some implementations, the PTH compound is a peptide having the amino acid sequence shown in SEQ ID NO: 10 (AZP-3601).

[0068] As used herein, the term "pharmaceutical composition" refers to a composition that contains one or more active ingredients, such as at least one PTH compound (e.g., AZP-3601), and one or more excipients, and any product that directly or indirectly results from the combination, complex formation or aggregation of any two or more components of the composition, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components.Thus, the pharmaceutical composition for use in the present invention encompasses any composition that is made by mixing one or more PTH compounds and pharmaceutically acceptable excipients.

[0069] As used herein, the term "excipient" refers to a diluent, adjuvant, or vehicle that is administered with a therapeutic agent, such as a drug or prodrug. Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an example of an excipient when the pharmaceutical composition is administered orally. Physiological saline and aqueous dextrose are examples of excipients when the pharmaceutical composition is administered intravenously. Physiological saline solution and aqueous dextrose and glycerol solution are used as liquid excipients for injectable solutions in certain embodiments. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, phenol, amino acids such as methionine and histidine (e.g., L-methionine and L-histidine), mannitol, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. If desired, the pharmaceutical compositions may contain minor amounts of wetting or emulsifying agents, for example, pH buffers such as acetate, succinate, Tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or surfactants such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or amino acids such as, for example, glycine, lysine, or histidine. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. The pharmaceutical compositions can be formulated as suppositories, with traditional binders and excipients such as triglycerides. Oral formulations can contain standard excipients such as pharmaceutical grades of mannitol, citrate, LLC, SNAC, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.Such compositions contain a therapeutically effective amount of drug or biologically active moiety together with a suitable amount of excipients to provide the form for proper administration to a patient.The formulation must be suitable for the mode of administration.As used herein, the term "liquid composition" refers to a mixture that includes a water-soluble PTH compound and one or more solvents such as water.

[0070] The term "drug" as used herein refers to a substance used in the treatment of hyperparathyroidism, e.g., a PTH compound. When a drug is conjugated to another moiety, the portion of the resulting product from which the drug originates is referred to as the "drug moiety."

[0071] As used herein, the term "prodrug" refers to a covalent conjugate in which a drug moiety is reversibly and covalently connected to a specific protecting group through a reversible linker moiety, also referred to as a "reversible prodrug linker moiety" or "reversible linker moiety", which includes a reversible linkage with a biologically active moiety, and the specific protecting group modifies or eliminates undesirable properties of the parent compound. This also includes enhancing desirable properties in the drug, and suppressing undesirable properties. The specific non-toxic protecting group is referred to as a "carrier". A prodrug releases the reversibly and covalently attached drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate that includes a drug moiety covalently and reversibly conjugated to a carrier moiety through a reversible linker moiety, and the covalent and reversible conjugation of the carrier to the reversible linker moiety is either directly or through a spacer. Such a conjugate releases the previously conjugated drug moiety in the form of a free unmodified drug.

[0072] As used herein, the term "reagent" refers to a compound that contains at least one functional group for reaction with a functional group of another compound or drug. It is understood that drugs that contain a functional group (such as a primary or secondary amine, or a hydroxyl functional group) are also reagents.

[0073] In certain embodiments, the pharmaceutical composition of the present invention has a pH between pH 3 and pH 8, inclusive. In certain embodiments, the pharmaceutical composition has a pH between pH 4 and pH 6, inclusive. In certain embodiments, the pharmaceutical composition has a pH between pH 4 and pH 5, inclusive. In some embodiments, the pharmaceutical composition has a pH of 5.6 + / - 0.3.

[0074] In certain embodiments, pharmaceutical composition is liquid or suspension composition.It is understood that pharmaceutical composition is liquid composition when PTH compound is water-soluble, and is suspension formulation when PTH compound is water-insoluble.In certain embodiments, pharmaceutical composition is dry formulation that is reconstituted before administration to patient.

[0075] Such liquid, suspension, dry or reconstituted pharmaceutical compositions contain at least one excipient. Excipients used in parenteral formulations include, for example, buffers, osmolality regulators, preservatives, stabilizers, anti-absorption agents, oxidation protectants, thickeners / viscosities (1.09 mPa for both concentrations of active (250 and 500 μg / mL) * s) enhancer, or other auxiliary. However, in some cases, one excipient may have two or three functions. In certain embodiments, at least one excipient is (i) a buffering agent: a physiologically acceptable buffering agent that maintains the pH in the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, pyruvate; Mg(OH) 2or antacids such as ZnCCfi may also be used; (ii) osmolality regulators: minimize pain that may result from cell damage due to osmolarity differences at the injection site; glycerin and sodium chloride are examples; effective concentrations can be determined by osmolarity measurements using an assumed osmolarity of 282-330 mOsmol / kg for serum (in some cases, the osmolarity may be in between); (iii) preservatives and / or antimicrobial agents: multi-dose parenteral formulations require the addition of preservatives in sufficient concentrations to minimize the risk of the patient becoming infected upon injection, and corresponding regulatory requirements have been established; typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride; (iv) stabilizers: stabilization is achieved by enhancing the ability to stabilize proteins. , by destabilization of denatured states or by direct binding of excipients to the protein; stabilizers may be amino acids, e.g., alanine, arginine, aspartic acid, glycine, histidine, lysine, proline, sugars, e.g., glucose, sucrose, trehalose, polyols, e.g., glycerol, mannitol, sorbitol, salts, e.g., potassium phosphate, sodium sulfate, chelating agents, e.g., EDTA, hexaphosphates, ligands, e.g., divalent metal ions (zinc, calcium, etc.), other salts, or organic molecules, e.g., phenol derivatives; in addition, oligomers or polymers, e.g., cyclodextrin, dextran, dendrimers, PEG, or PVP, or protamine, or HSA, may be used; (v) anti-absorption agents: mainly ionic or non-ionic surfactants, or other proteins, or soluble polymers are used to competitively coat or absorb to the inner surface of the formulation container; e.g., poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG polyhistidine, BSA and HSA, and gelatin;The selected concentration and type of excipient will depend on the effect to be avoided, but typically a monolayer of surfactant will form at the interface just above the CMC value; (vi) oxidation protectants: antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, and vitamin E; chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid may also be used; (vii) thickening or viscosity enhancing agents: in the case of suspensions, used to retard settling of particles in vials and syringes, facilitate mixing and resuspension of particles, and make suspensions easier to inject (i.e., low forces on the syringe plunger);Suitable thickening or viscosity enhancing agents are, for example, carbomer thickeners such as Carbopol 940, Carbopol Ultrez 10, cellulose derivatives such as hydroxypropyl methylcellulose (hypromellose, HPMC) or diethylaminoethylcellulose (DEAE or DEAE-C), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthan, Satia gum UTC carrageenans such as 30, aliphatic poly(hydroxy acids), such as poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and copolymers thereof (PLGA), terpolymers of D,L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks constituting a poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblock (e.g., Pluronic®), polyetherester copolymers, such as polyethylene glycol terephthalate / polybutylene terephthalate copolymers, sucrose acetate isobutyrate (SAIB), dextran or derivatives thereof, combinations of dextran and PEG, polydimethylsiloxanes, collagen, chitosan , polyvinyl alcohol (PVA) and derivatives, polyalkylimides, poly(acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAGs), e.g., dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan, ABA triblock or AB block copolymers composed of a hydrophobic A block, such as polylactide (PLA) or poly(lactide-co-glycolide) (PLGA), and a hydrophilic B block, such as polyethylene glycol (PEG) or polyvinylpyrrolidone; such block copolymers and the above-mentioned poloxamers may exhibit inverse thermogelation behavior (fluid state at room temperature for ease of administration and gel state above the sol-gel transition temperature at body temperature after injection);(vii) Diffusion agents: components of the extracellular matrix in the interstitial space, such as, but not limited to, hyaluronic acid, which regulate the permeability of connective tissue by hydrolysis of polysaccharides found in the intracellular space of connective tissue; Diffusion agents, such as, but not limited to, hyaluronidase, which temporarily reduce the viscosity of the extracellular matrix and facilitate the diffusion of the injected drug; and (ix) other auxiliary agents: e.g., wetting agents, viscosity adjusting agents, antibiotics, hyaluronidase; acids and bases, e.g., hydrochloric acid and sodium hydroxide, which are necessary auxiliary agents for pH adjustment during preparation;

[0076] The administration of the PTH compound as defined herein may be by any suitable means that results in a concentration of the compound that treats the subject and disease state.In some examples, the PTH compound may contain any suitable carrier material in any suitable amount, and is generally present in an amount of 0.025% to 1% by weight of the total weight of the composition / dose.The composition may be in the form of, for example, a tablet, an ampoule, a capsule, a pill, a powder, a granule, a suspension, an emulsion, a solution, a gel, including a hydrogel, a paste, an ointment, a cream, a plaster, a drench, an osmotic delivery device, a suppository, an enema, an injection, an implant, a spray, or an aerosol. Pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., 2000, edited by A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, which are incorporated herein by reference).

[0077] Pharmaceutical compositions may be formulated to release active compound immediately upon administration or at any predetermined time or period after administration.The latter type of composition is generally known as controlled release formulation, which includes: (i) formulation that creates substantially constant concentration of the agent of the present invention in the body for an extended period of time; (ii) formulation that creates substantially constant concentration of the agent of the present invention in the body for an extended period of time after a predetermined lag time; (iii) formulation that sustains the action of the agent for a predetermined period of time by maintaining the effective level of the agent in the body relatively constant, while minimizing the undesirable side effects related to fluctuations in the plasma level of the agent (sawtooth kinetic pattern); (iv) formulation that localizes the action of the agent adjacent to or within the desired tissue or organ, for example, the spatial location of the controlled release composition; (v) formulation that achieves the convenience of dosing, for example, administering the composition once a week or once every two weeks; and (vi) formulation that targets the action of the agent by using carriers or chemical derivatives that deliver the compound to a specific target cell type. Administration of the compound in the form of a controlled release formulation is particularly preferred for compounds that have a narrow absorption window in the gastrointestinal tract or a relatively short biological half-life.

[0078] In order to obtain controlled release, in which the release rate exceeds the metabolism rate of the compound in question, any of many strategies can be pursued.In one example, controlled release is obtained by appropriate selection of various formulation parameters and components, including, for example, various types of controlled release compositions and coatings.Therefore, compound is formulated with suitable excipients into pharmaceutical composition that releases compound in a controlled manner upon administration.Examples include single or multiple unit tablet or capsule composition, oily solution, suspension, emulsion, microcapsule, molecular complex, microsphere, nanoparticle, patch and liposome.

[0079] Compositions comprising the PTH compounds described herein may be administered parenterally, by injection, infusion or implantation (subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) in dosage forms, formulations containing conventional non-toxic pharmacologic carriers and adjuvants, or via suitable delivery devices or implants.

[0080] In some embodiments, the pharmaceutical compositions of the invention are provided in a prefilled pen.

[0081] In some embodiments, the prefilled pen contains about 20 μg to about 750 μg, about 20 μg to about 500 μg, about 20 μg to about 250 μg, or about 320 μg to about 100 μg of the PTH compound.

[0082] Compositions for parenteral use may be provided in unit dosage form (e.g., in single-dose ampoules) or in vials containing several doses, to which suitable preservatives may be added (see below). The compositions may be in the form of solutions, suspensions, emulsions, injection devices, or delivery devices for implantation, or may be presented as dry powders to be reconstituted with water or another suitable vehicle before use. Apart from the active agent, the compositions may contain suitable parenterally acceptable carriers and / or excipients. The active agent may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, etc. for controlled release. Furthermore, the compositions may contain suspending agents, solubilizing agents, stabilizing agents, pH adjusting agents, osmotic adjusting agents, and / or dispersing agents.

[0083] As indicated above, the pharmaceutical compositions according to the invention may be in a form suitable for sterile injection. To prepare such compositions, a suitable active agent is dissolved or suspended in a parenterally acceptable liquid vehicle. Among the acceptable vehicles and solvents that may be used are water, water adjusted to a suitable pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, dextrose solution, and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate). In cases where one of the compounds is poorly or only slightly soluble in water, a solubility enhancer or solubilizer may be added, or the solvent may contain 10-60% w / w propylene glycol, or the like. EXAMPLES

[0084] Example 1 Effect of AZP-3601 on serum calcium levels in HP PTX mouse model Enhanced effects on serum calcium were observed in preclinical mouse models in which HP was induced by parathyroidectomy or PTX, where AZP-3601 was more potent and effective than native PTH(1-34) in restoring and maintaining blood calcium and phosphate levels. In Figure 1, the black line shows the effect of PTX in mice, resulting in serum calcium levels well below normal levels. A single dose of PTX mice with 200 μg / kg PTH(1-34) (blue line) was observed to reduce serum calcium levels due to its short half-life and R of the PTH1 receptor. 0 Consistent with its weaker interaction with the PTH1 conformation, AZP-3601 caused a transient elevation of serum calcium. In contrast, single dosing of PTX mice with 20, 40, or 80 μg / kg (yellow, orange, and brown lines, respectively) inhibited the R 0Consistent with its strong interaction with the conformation, AZP-3601 has a short half-life comparable to that of PTH(1-34), yet it induced a dose-related normalization of serum calcium that was sustained for up to 72 hours.

[0085] Example 2 Effect of AZP-3601 on serum calcium levels in the HP TPTX rat model Thyroid-parathyroidectomized or TPTX rats were treated with daily subcutaneous injections of AZP-3601 at doses ranging from 3.8 μg / kg / day to 30.7 μg / kg / day. Treatment continued for 28 days. Long-term treatment with AZP-3601 caused a dose-dependent gradual normalization of serum calcium levels and reduced blood phosphate levels in TPTX rats. The increase in calcium accumulated over time (over the first 15-21 days) but became more constant thereafter. This indicates the development of a steady-state effect (Figure 2). Due to the cumulative effect, lower doses of AZP-3601 were required to eventually increase blood calcium levels to the normal range compared to the dose required with a single injection. With repeated dosing, a dose of 7.7 μg / kg (1.8 nmol / kg) / day was found to be optimal. This dose normalized blood calcium without increasing urinary calcium excretion and without producing any significant changes in bone. In TPTX rats injected once daily with native PTH(1-84), there was no sustained increase in blood calcium levels and only a slight reduction in blood phosphate levels compared to levels in vehicle-treated TPTX rats (Figure 2).

[0086] Example 3 Evaluation of AZP-3601 on urinary calcium levels in a mouse model of HP PTX In preclinical studies of PTX mice, a single dose of AZP-360 resulted in the maintenance of normal levels of urinary calcium excretion despite a marked increase in serum calcium levels (Figure 3). This data contrasts with the elevated urinary calcium levels that would be expected from other approaches to increasing serum calcium levels, such as dietary supplementation with inorganic calcium and vitamin D or treatment with continuous infusion of native PTH.

[0087] Example 4 Evaluation of repeated doses of AZP-3601 on urinary calcium in the HP TPTX rat model To examine the effect of repeated dosing with AZP-3601 on urinary calcium levels, TPTX rats were treated with daily subcutaneous administration of AZP-3601 at doses ranging from 3.8 to 30.7 μg / kg / day. As additional controls, separate groups of TPTX rats that received daily injections of either native PTH(1-84) or vehicle, and groups of normal (with intact thyroid and parathyroid glands or sham) rats, were injected with vehicle. Despite the increases in serum calcium induced by AZP-3601, there was no significant increase in urinary calcium, except at the highest dose of 30.7 mg / kg / day, which induced overt hypercalcemia. The observed increases in urinary calcium excretion with higher doses were normal renal responses to excrete excess blood calcium (Figure 4).

[0088] Example 5 : Evaluation of the biological activity of AZP-3601 in non-human primates To further explore how the potent and sustained biological activity induced by AZP-3601 translates into potential clinical benefit for hypothyroid patients, its activity was examined in normal cynomolgus monkeys, a species that is very close to humans and most relevant for initial human dose selection. A single injection of AZP-3601 was administered to normal cynomolgus monkeys. AZP-3601 was detectable in plasma only for up to 1 hour after dosing, but the effect on serum calcium persisted for several days. The dissociation between the pharmacokinetic profile and pharmacodynamic effect was due to the R of the PTHI receptor.0 Contrary to the prolonged signaling caused by the strong interaction of AZP-3601 with the conformation, this is due to the short circulating half-life of AZP-3601. AZP-3601 also increased blood calcium levels in a dose-dependent manner. As can be seen in panel A of FIG. 5, a significant increase in blood calcium was observed 24 hours after injection of 1.1 μg AZP-3601 / kg (0.25 nmol / kg), with the maximum effect observed at 2.1 μg / kg (0.5 nmol / kg). With higher doses of 2.1 and 4.2 μg AZP-3601 / kg (0.5 and 1 nmol / kg), a significant increase in blood calcium levels was observed as early as 12 hours after injection, and remained significantly elevated up to 72 hours after a single injection.

[0089] In a second study, illustrated in panel B of FIG. 5, monkeys were injected with a single dose of either 95 μg / kg native PTH(1-84), 42 μg / kg native PTH(1-34), or 42.7 μg / kg AZP-3601, which were equivalent to a 10 nmole / kg dose adjusted for the molecular weight of the individual compounds. In addition, a lower dose of 10.7 μg AZP-3601 / kg (2.5 nmole / kg) was also tested. The two doses of AZP-3601 similarly induced an increase in blood calcium levels well above the normal range, representing overt hypercalcemia, which remained elevated for at least four days after injection. In contrast, equivalent doses of the native PTH compounds PTH(1-84) and PTH(1-34) only moderately increased blood calcium, with calcium levels returning to baseline within 24 hours. In these studies in normal cynomolgus monkeys, AZP-3601 was approximately 40-fold more potent than either native PTH(1-84) or PTH(1-34) in raising serum calcium and produced a longer lasting effect (days for AZP-3601 vs. hours for native PTH).

[0090] Example 6: Direct comparison of the distal femur in TPTX rats after 14 days of treatment with either daily PTH(1-34) injections at doses that normalize serum calcium, continuous PTH(1-34) infusion, or daily AZP-3601 injections To directly compare the effects of daily subcutaneous injections of AZP-3601 with daily subcutaneous injections and continuous infusion of PTH(1-34), dose levels for each regimen that normalized serum calcium levels in TPTX rats were utilized. These doses corresponded to 50 nmole / kg / day (205 μg / kg / day) for daily injected PTH(1-34), 3 nmole / kg / day (12.3 μg / kg / day) for continuously infused PTH(1-34), and 1 nmole / kg / day (4.2 μg / kg / day) for daily injected AZP-3601. After 14 days of treatment, femurs were harvested and examined for bone mineral density (BMD) by quantitative computed tomography. A significant increase in BMD was observed with daily injections of PTH(1-34), a significant decrease in BMD was observed with continuously infused PTH(1-34), and no significant effect on BMD was observed with daily injections of AZP-3601. These results with PTH(1-34) suggest that the R 0 This is likely the result of the combined effects of its enhanced signaling due to its strong interaction with the conformation and its short circulating half-life, and is highly consistent with previous studies involving intermittent and continuous administration of native PTH, providing evidence of an intrinsic neutral effect of AZP-3601 (Figures 6A-6C).

[0091] Example 7 Evaluation of AZP-3601 on bone mineral density in the HP TPTX rat model To examine the effects of repeated dosing with AZP-3601, TPTX rats were treated with daily subcutaneous injections of either vehicle or AZP-3601 at doses ranging from 3.8 to 30.7 μg / kg / day (0.9 to 7.2 nmole / kg / day). As additional controls, separate groups of TPTX rats that received daily injections of native PTH(1-84), and groups of normal (with intact thyroid and parathyroid glands, or sham) rats, were injected with vehicle. The results of this study are presented in Figure 7. Long-term treatment with AZP-3601 showed no effect on bone. Both whole femurs and lumbar spine were analyzed using a technique called dual-energy X-ray absorptiometry, or DXA, which measures BMD. This analysis revealed that there was no significant effect of AZP-3601 treatment compared to bone from animals treated with vehicle alone. In contrast, TPTX rats that received a single daily injection of native PTH(1-84) showed a statistically significant increase in BMD in both the lumbar spine and total femur (p<0.05). The AZP-3601 treatment group demonstrated no significant differences in bone structure using micro-computed tomography techniques.

[0092] In contrast, in a reported study (Holten-Andersen et al. JBMR 34:2075, 2019, ref. 20) that also used TPTX rats treated for a similar length of time with the TransCon® formulation of native PTH(1-34), this resulted in a continuous non-pulsed infusion-like pharmacokinetic profile, and a significant decrease in BMD was observed compared to both sham-operated TPTX rats and TPTX rats treated with vehicle alone. Previous third-party studies have similarly demonstrated that intermittent administration of native PTH increased BMD, while continuous non-pulsed infusions led to a decrease in BMD. The impact of continuous non-pulsed exposure to native PTH compounds on bone can also be clearly observed in certain pathologies, such as hypercalcemia of malignancy, where continuous non-pulsed production of PTH-related peptide or PTHrP, which also acts on the PTH1 receptor, induces a highly significant decrease in BMD over only a few months.

[0093] Example 8 AZP-3601 has no effect on bone parameters after chronic treatment in non-human primates To further explore the effects of long-term AZP-3601 treatment on bone, both 13-week and 36-week studies were conducted in non-human primates (NHPs), which are considered a relevant species for the effects of AZP-3601 on serum calcium. Groups of three or four cynomolgus monkeys of each sex were given daily subcutaneous injections of either vehicle or AZP-3601 at doses of 1, 2.5 or 10 μg / kg, as outlined in Table 1, for either 13 or 39 weeks. The doses selected are either within or significantly exceed the expected therapeutic dose range for cHP patients.

[0094] [Table 2]

[0095] 13-week trial o Ex vivo bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) at 13 weeks; o Bone histopathology at 13 weeks. 39-week trial o Serum bone biomarkers at baseline and weeks 4, 8, 13, 26 and 39; o In-life BMD by quantitative computed tomography (qCT) at baseline and at weeks 26 and 39; o Bone histopathology at 39 weeks.

[0096] At the end of the 13-week study, the right femur, right tibia and L4 lumbar vertebrae were collected from 3 animals / group / sex, and bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The left femur was submitted for histopathology examination. There was no evidence of any treatment-related effects on either BMD or histopathology. In the 39-week study, blood samples were collected from 4 animals / group / sex before treatment and during weeks 4, 8, 13, 26 and 39 of treatment for the measurement of bone biomarkers. The viable BMD of the left femur, left tibia and L4 lumbar vertebrae was measured by quantitative computed tomography (qCT) before treatment and during weeks 36 and 39 of treatment (Figures 9A, 9B, 9C, 9D, 9E and 9F). At the end of the treatment period, the femur was processed for histopathology examination.

[0097] Analysis of blood samples for the anabolic bone biomarker N-terminal propeptide of collagen type 1 (P1NP), and the catabolic bone biomarker C-terminal telopeptide (CTx), revealed no treatment-related changes at any time in either gender (Figures 8A, 8B, 8C, and 8D). Before treatment, BMD was uniform among all groups for all three bone sites examined. Over the course of the study, there were no statistically significant changes in BMD compared to pretreatment values, regardless of gender or AZP-3601 treatment. Subsequent histological examination of the femurs revealed no notable findings.

[0098] This apparently neutral effect of AZP-3601 on bone is unique and is due to its R-dependent activation of the PTHI receptor. 0 This may be due to its strong binding to the conformation, its short circulatory half-life, and its greatly enhanced and prolonged biological effect allowing the use of substantially lower doses.

[0099] In HP patients, as observed in population studies, there is a precarious balance between the potentially protective effect of increased BMD on the widespread abnormal bone microarchitecture in patients, which translates into a neutral risk of fracture. However, any treatment or condition that reduces BMD has the potential to shift the balance in favor of abnormal microarchitecture and may increase the risk of fracture. As a result, treatments with a neutral effect on bone can be seen as a substantial benefit in this patient population.

[0100] The results presented in Examples 6, 7 and 8 demonstrate the absence of adverse effects of long-term AZP-3601 treatment on bone and further substantiate the potential of AZP-3601 as a treatment for HP that does not compromise bone integrity.

[0101] Example 9: Evaluation of the safety and tolerability of PTH compounds after a single dose and multiple ascending doses over a 2-week period administered by subcutaneous (sc) injection in healthy subjects Part A: This part of the evaluation was a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study in healthy male subjects to evaluate the safety and tolerability, PK and PD of a PTH compound having SEQ ID NO: 10 (AZP-3601). Subjects were screened 28 days to 3 days prior to study drug administration. Up to seven sequential cohorts were planned for this part of the study. The first cohort included four subjects, three subjects randomized to receive AZP-3601 and one subject randomized to receive placebo. Each sequential cohort included eight subjects (six receiving AZP-3601 and two receiving placebo in a randomized, double-blind fashion). Subjects in Part A received the study drug at the clinical site as a single sc abdominal injection in the morning. The actual doses administered in the SAD part in healthy volunteers are shown below. Cohort A1: A single sc dose of 5 μg AZP-3601 (n=3) or matching placebo (n=1) on day 1 Cohort A2: A single sc dose of 10 μg AZP-3601 (n=6) or matching placebo (n=2) on day 1 Cohort A3: A single sc dose of 20 μg AZP-3601 (n=6) or matching placebo (n=2) on day 1 Cohort A4: A single sc dose of 40 μg AZP-3601 (n=6) or matching placebo (n=2) on day 1 Cohort A5: A single sc dose of 60 μg AZP-3601 (n=6) or matching placebo (n=2) on day 1 Cohort A6: A single sc dose of 120 μg AZP-3601 (n=6) or matching placebo (n=2) on day 1 Cohort A7: A single sc dose of 90 μg AZP-3601 (n=6) or matching placebo (n=2) on day 1

[0102] A median albumin-corrected peak serum calcium level of ≥ 10.5 mg / dL (2.6 mmol / L) based on blinded data (AZP-3601-treated subjects only) or an albumin-corrected peak serum calcium level of ≥ 12 mg / dL (3.0 mmol / L) in at least one subject was used as a general guideline for performing smaller dose escalations. Within each cohort, subjects were dosed essentially as follows: Two sentinel subjects were dosed on the first dosing date (one subject receiving AZP-3601 and one subject receiving placebo). Serum calcium was monitored until levels were equal to baseline values ​​and / or within normal range. There was an interval of at least 7 days between the last dose in one cohort and the first dose in the next cohort. Each subject participated in only one cohort during the study.

[0103] Part B: This part of the evaluation was a randomized, double-blind, placebo-controlled, multiple ascending dose (MAD) study in healthy male or non-childbearing female subjects to evaluate the safety and tolerability, PK, and PD of AZP-3601. Subjects were screened 28 days to 3 days prior to the (initial) study drug administration. Four sequential cohorts were planned for this part of the study. Each cohort included 10 subjects (8 receiving AZP-3601 and 2 receiving placebo in a randomized fashion). Subjects in Part B received the study drug at the clinical site as sc abdominal injections in the morning daily for 14 days (with rotation of injection site on all dosing days). The actual doses administered in the MAD part in healthy volunteers are shown below. Cohort B1: multiple sc doses of 10 μg AZP-3601 (n=8) or matching placebo (n=2) once daily (qd) on days 1 through 14 Cohort B2: multiple sc doses of 20 μg AZP-3601 (n=8) or matching placebo (n=2) qd on days 1 through 14 Cohort B3: multiple sc doses of 40 μg AZP-3601 (n=8) or matching placebo (n=2) qd on days 1 through 14 Cohort B4: multiple sc doses of 60 μg AZP-3601 (n=8) or matching placebo (n=2) qd on days 1 through 14 Cohort B5: multiple sc doses of 80 μg AZP-3601 (n=8) or matching placebo (n=2) qd on days 1 through 14

[0104] Subjects received study drug qd for a total period of 14 days to obtain steady state of PD parameters including serum and urinary calcium. Serum calcium was monitored until levels were equal to baseline values ​​and / or within normal range. Part B began after completion of the first three cohorts of Part A. A median albumin-corrected peak serum calcium level of ≥ 10.5 mg / dL (2.6 mmol / L) based on blinded data (AZP-3601-treated subjects only) or an albumin-corrected peak serum calcium level of ≥ 12 mg / dL (3.0 mmol / L) in at least one subject was used.

[0105] FIG. 10 shows that AZP-3601 treatment produced a clear dose-dependent increase in mean albumin-adjusted serum calcium values ​​from baseline compared to placebo control. The normal physiological diurnal variation in albumin-adjusted serum calcium was gradually attenuated by 5 μg and 10 μg AZP-3601 and completely eliminated by 20 μg. At a dose of 40 μg AZP-3601, mean albumin-adjusted serum calcium values ​​increased significantly, but remained within the normal laboratory range and elevated for at least 24 hours after dosing. A dose-dependent decrease in mean endogenous serum PTH was observed, which correlated significantly with the concomitant increase in mean serum calcium. These data provide evidence of a pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours after a single dose.

[0106] Example 10: Evaluation of the safety and tolerability of PTH compounds after a single dose and multiple ascending doses over a 4 week period administered by sc injection in subjects with HP Part C: Part C of the evaluation was an open-label, multiple ascending dose (MAD) study in male or female subjects with hypoparathyroidism (HP) during standard of care treatment (treatment with oral calcium and active vitamin D) to evaluate the safety and tolerability, PK and PD of AZP-3601. Up to two cohorts of approximately 12 patients each were planned for this part of the study. Prior to the treatment period, there was an optimization period of up to 8 weeks during which oral calcium and active vitamin D doses were adjusted to achieve baseline target ranges of albumin-corrected serum calcium (7.8-9.0 mg / dL, i.e., 1.95-2.25 mmol / L), thus ensuring a close baseline for all patients. During this optimization period, any serum 25-hydroxyvitamin D (native vitamin D) and / or magnesium deficiencies were corrected. During the treatment period, patients in part C received AZP-3601 as daily sc abdominal injections for 28 days (with rotation of injection site on all dosing days). The doses of oral calcium and active vitamin D supplementation were reduced during the first 14 days of treatment while maintaining albumin-corrected serum calcium in the target range (7.8-9.0 mg / dL, i.e., 1.95-2.25 mmol / L). Reductions in both oral calcium and active vitamin D supplementation were made using a stepwise approach until active vitamin D doses were eliminated and oral calcium doses were reduced to 500 mg / day or less. Based on animal data, serum calcium was expected to increase progressively after repeated dosing of AZP-3601, and PD steady state was expected to be observed within the first 5 days of dosing. Alternating reductions in the doses of oral calcium and active vitamin D supplementation were therefore made near steady state based on pre-dosing albumin-corrected serum calcium values. The following treatments were administered in Part C in an open-label format: Cohort C1: multiple sc doses of 20 μg AZP-3601 qd from day 1 to day 28 (n=12) (dose escalation of AZP-3601 to 40 μg was allowed from day 14 onwards) Cohort C2: Multiple sc doses of AZP-3601 fixed dose of 10 μg qd from day 1 to day 28 (n=12) (AZP-3601 dose could be increased from day 14 onwards to a fixed dose of 20 μg)

[0107] During the expansion phase, patients had their AZP-3601 dose increased in 10 μg increments up to a maximum dose of 60 μg (Cohort 1) and 80 μg (Cohort 2).

[0108] Example 11: Evaluation of the safety and tolerability of PTH compounds during a two-month treatment expansion period in subjects with HP The expansion phase began immediately after the day 28 visit of the main treatment period. Patients received AZP-3601 as daily sc injections for 56 days (2 months) beginning on day 29 (with rotation of injection site with each day of dosing). The goal was to optimize AZP-3601 dosing across the dose range while safely lowering oral calcium and active vitamin D doses as much as possible and maintaining albumin-corrected serum calcium within the target range of 7.8-9.0 mg / dL (1.95-2.25 mmol / L). For patients taking minimal or no supplemental calcium (≤500 mg / day) and no vitamin D on day 28, the AZP-3601 dose from the previous 14 days of treatment (Part C, main treatment period) was maintained and adjusted if necessary during the expansion phase. For patients still taking active vitamin D and / or oral calcium >500 mg / day on day 28, a gradual reduction in supplementation was made while increasing the dose of AZP-3601. From day 29 onwards, patients continued at the same dose of AZP-3601 as on day 28, and then individual titration of AZP-3601 was initiated around day 30, with patients having their AZP-3601 dose adjusted at any time during the expansion phase. Patients could have their AZP-3601 dose increased as previously defined, with the goal of achieving or maintaining albumin-corrected serum calcium within the target range of 7.8-9.0 mg / dL (1.95-2.25 mmol / L). AZP-3601 doses were adjusted downward at any time to maintain albumin-corrected serum calcium within the target range or if necessary for any safety concerns. Once patients achieved stable albumin-corrected serum calcium on the minimum dose of replacement, they were maintained on that dose of AZP-3601.

[0109] Figures 11A and 11B show that administration of AZP-3601 at a starting dose of 20 μg / day (Figure 11A) and 10 μg / day (Figure 11B) in subjects who had completed the expansion period allowed cessation of active vitamin D / calcitriol administration within 2 weeks of initiating treatment.

[0110] Figures 12A and 12B show that administration of AZP-3601 at a starting dose of 20 μg / day (Figure 12A) and 10 μg / day (Figure 12B) in subjects who had completed the expansion period allowed a sustained reduction in oral calcium supplementation below 500 mg / day (dotted line). In cohort 2, cessation of oral calcium supplementation was delayed and required titration due to the lower starting dose, supporting a dose-related effect.

[0111] Figures 13A and 13B show that administration of AZP-3601 at a starting dose of 20 μg / day (Figure 13A) and 10 μg / day (Figure 13B) in subjects who completed the expansion period maintained mean serum calcium within the target range throughout the 84-day study. These results demonstrate that administration of AZP-3601 allows for rapid cessation of standard treatment for HP.

[0112] Figures 14A and 14B show that administration of AZP-3601 induced rapid, prolonged, and sustained reduction and normalization of mean 24-hour urinary calcium throughout the treatment period of the study in both cohorts. Results presented in Figures 15A and 15B show that administration of AZP-3601 induced rapid, extensive, and sustained normalization of 24-hour urinary calcium in both cohorts in 12 of 13 subjects with elevated urinary calcium at baseline.

[0113] Figures 16A-16D show that treatment with AZP-3601 induced a progressive increase in both anabolic and catabolic bone biomarkers to median normal levels from 4 to 8 weeks. The data presented here also demonstrate that AZP-3601 did not increase any of the mean bone markers above the upper normal limit, thereby supporting the working hypothesis that AZP-3601's mechanism of action targets urinary calcium resorption rather than bone resorption. This is a differentiating factor, as up to 17% of HP patients have osteopenia or osteoporosis and 53% are pre- and post-menopausal women. Bone mineral density (BMD) and trabecular bone score (TBS) remained stable in both cohorts of subjects (Figures 17A and 17B). These results demonstrate that administration of AZP-3601 does not impair bone integrity. Figures 18A and 18B show the effect of AZP-3601 administration on Z-scores and T-scores at various bone sites. Consistent with the balanced increase in bone biomarkers, the data demonstrate that Z-scores and T-scores remained stable, including in patients with osteopenia. The T-score data further indicate that 43% of patients (6 of 14 patients) were osteopenic at baseline in at least one anatomical site.

[0114] All references cited herein and the references therein, where appropriate for teaching additional or alternative details, features, and / or technical background, are hereby incorporated by reference in their entirety.

[0115] While the present disclosure has been particularly shown and described with reference to certain embodiments, it will be appreciated that variations of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications, and various presently unforeseen or unanticipated substitutions, modifications, variations or improvements therein may be subsequently made by those skilled in the art and are also intended to be encompassed by the following claims.

[0116] List of references 1. Bilezikian J, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 9th ed. Washington, DC: American Society for Bone and Mineral Research; 2019. 2. Gafni RI and Collins MT. Hypoparathyroidism. N Engl J Med. 2019;380(18):1738-47. 3. Rubin MR, Dempster DW, et al. Dynamic and Structural Properties of the Skeleton in Hypoparathyroidism. 2008 Dec; 23(12):2018-2024. 4. Vokes TJ. Quality of Life in Hypoparathyroidism. Endocrinol Metab Clin North Am. 2018;47(4):855-64. 5. Mannstadt M, Clarke BL, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013 Dec;1(4):275-83. 6. Winer KK. Does PTH Replacement Therapy Improve Quality of Life in Patients With Chronic Hypoparathyroidism? J Clin Endocrinol Metab. 2018 Jul 1;103(7):2752-2755. 7. Bi R, Fan Y, Lauter K, et al. Diphtheria Toxin- and GFP-Based Mouse Models of Acquired Hypoparathyroidism and Treatment With a Long-Acting Parathyroid Hormone Analog. J Bone Miner Res. 2015;31(5):975-84. 8. Shimizu M, Joyashiki E, Noda H, et al. Pharmacodynamic Actions of a Long-Acting PTH Analog (AZP-3601) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys. J Bone Miner Res. 2016;31(7):1405-12. 9. Aliya A Khan, Mishaela R Rubin, et al. Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3. PaTHway Trial. J Bone Miner Res. 2023;38(1):14-25. 10. Lars Holten-Andersen, Susanne Pihl, Caroline E Rasmussen, et al. Design and Preclinical Development of TransCon PTH, an Investigational Sustained-Release PTH Replacement Therapy for Hypoparathyroidism. J Bone Miner Res. 2019 Nov;34(11):2075-2086. 11. Aliya A Khan, Mishaela R Rubin, Peter Schwarz, et al. Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial. J Bone Miner Res. 2023 Jan;38(1):14-25. 12. Clarke B, Khan AA, Rubin MR, et al. Long-Term Efficacy and Safety of TransCon TM PTH in Adults with Hypoparathyroidism: 52-Week Results From the Open-Label Extension of the Phase 3 PaTHway Trial. Paper presented at: the Endocrine Society annual meeting. June 15 - 18, 2023. 13. Underbjerg et al. Postsurgical hypoparathyroidism--risk of fractures, psychiatric diseases, cancer, cataract, and infections. JBMR 29:2504, 2014. 14. Underbjerg et al., The Epidemiology of Nonsurgical Hypoparathyroidism in Denmark: A Nationwide Case Finding StudyJBMR 30:1738, 2015). 15. Chawla et al. Vertebral Fractures and Bone Mineral Density in Patients With Idiopathic Hypoparathyroidism on Long-Term Follow-Up. JCEM 102:251, 2017. 16. Mendonea et al. Increased vertebral morphometric fracture in patients with postsurgical hypoparathyroidism despite normal bone mineral density. Endocrine Disorders 13:1, 2013. 17. Tam et al. Parathyroid Hormone Stimulates the Bone Apposition Rate Independently of Its Resorptive Action: Differential Effects of Intermittent and Continuous Administration. Endocrinology 110:505, 1982. 18. Dobnig and Turner. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 138: 4607, 1997. 19. Horwitz et al. A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover. J Bone Miner Res 26 :2287, 2011. 20. Holten‐Andersen et al. Design and Preclinical Development of TransCon PTH, an Investigational Sustained-Release PTH Replacement Therapy for Hypoparathyroidism. JBMR 34:2075, 2019

Claims

1. A pharmaceutical composition for the management and / or treatment of hypoparathyroidism (HP) in a subject, comprising a PTH compound having the amino acid sequence shown in SEQ ID NO: 10, and administered at a dose of 10 μg / day to 120 μg / day of the PTH compound.

2. The pharmaceutical composition according to claim 1, wherein administration of the PTH compound maintains or improves bone health.

3. The pharmaceutical composition according to claim 1, wherein the dose of the PTH compound is 10 μg / day to 100 μg / day, or 10 μg / day to 80 μg / day.

4. The pharmaceutical composition according to claim 1, wherein the subject is gradually withdrawn from standard treatment for HP from the time of administration of the initial dose of the PTH compound.

5. The pharmaceutical composition according to claim 4, wherein the HP of the subject is withdrawn from standard treatment within 12 weeks, 10 weeks, 6 weeks, 4 weeks, or 2 weeks from the time of administration of the initial dose of the PTH compound.

6. The pharmaceutical composition according to claim 4, wherein discontinuing the subject from standard treatment for HP involves reducing the administration of the standard treatment until the administration of the dose of the PTH compound results in a stable albumin-corrected serum calcium level in the subject.

7. The pharmaceutical composition according to claim 6, wherein the stable albumin-corrected serum calcium level is 8.3 mg / dL to 10.6 mg / dL.

8. The pharmaceutical composition according to claim 1, wherein the subject is a subject having hypercalciuria.

9. The pharmaceutical composition according to claim 8, wherein administration of the PTH compound normalizes urinary calcium levels in subjects with hypercalciuria.

10. The pharmaceutical composition according to claim 1, wherein the subject is a woman in the perimenopausal or postmenopausal period.

11. The pharmaceutical composition according to claim 10, wherein the subject further suffers from osteopenia or osteoporosis.

12. The pharmaceutical composition according to claim 1, wherein the administration is by subcutaneous injection using a pen-type syringe.

13. An injection pen comprising the pharmaceutical composition described in claim 1.

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