JP-7855040-B2 - PTH Prodrug

Inventors

• スプローエ，ケネット
• クレーマン，フェリックス
• マイトロ，ギラウメ
• クルシュ，マティアス
• ヴェッケ，トーマス
• ゼットラー，ヨアヒム

Assignees

• アセンディス ファーマ ボーン ディジージズ エー／エス

Dates

Publication Date

20260507

Application Date

20240906

Priority Date

20160301

Claims (11)

1. Formula 31: (In the formula, PTH(1-34) is a parathyroid hormone having the amino acid sequence of SEQ ID NO: 51. N αs1 is the α-amino group of the N-terminal serine in SEQ ID NO: 51. 2x10 kDa PEG contains a branched polyethylene glycol polymer with two arms, each having a molecular weight of 10 kDa. A PTH prodrug having [a specific characteristic], or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a PTH prodrug according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one excipient.
3. The pharmaceutical composition according to claim 2 for subcutaneous administration to humans.
4. A syringe with a needle or a pen-type syringe comprising the PTH prodrug described in claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 2 or 3 .
5. A pharmaceutical product comprising the PTH prodrug according to claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2 or 3, for the treatment of hypoparathyroidism in a patient.
6. The pharmaceutical product according to claim 5 , for subcutaneous administration.
7. The pharmaceutical product according to claim 6 , wherein subcutaneous administration is performed using a pen-type syringe.
8. The pharmaceutical product according to claim 6 , wherein subcutaneous administration is performed using a syringe with a needle.
9. A pharmaceutical product according to any one of claims 5 to 8 , administered at intervals of at least 24 hours.
10. A pharmaceutical product according to any one of claims 5 to 9 , administered at intervals of one week.
11. A pharmaceutical product comprising a PTH prodrug according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2 or 3 , for parathyroid hormone replacement therapy that enables relief of symptoms associated with hypocalcemia, hypercalciuria, and hyperphosphatemia without causing hypercalcemia.

Description

This invention relates to PTH prodrugs, pharmaceutical compositions comprising such PTH prodrugs or pharmaceutically acceptable salts thereof, and the use thereof. Hypoparathyroidism is a rare endocrine disorder characterized by low serum calcium levels and inadequately low (insufficient) circulating parathyroid hormone levels, most often occurring in adults after thyroid surgery. Standard treatment involves active vitamin D analogues and calcium supplementation, which increases calcium and phosphorus absorption and serum levels to compensate for abnormally increased urinary calcium excretion. Hypoparathyroidism is currently the only severe endocrine condition in which the hormonal deficiency is generally not treated by hormone replacement therapy (PTH). A recent systematic study in Denmark investigated the prevalence of hypoparathyroidism, identifying over 2,000 patients and yielding a prevalence of approximately 24/100,000 of the population. Only a small fraction (2/100,000) of the identified patients had non-surgically caused hypoparathyroidism. These estimates are consistent with the latest USA data showing a similar prevalence for chronic hypoparathyroidism. Endogenous PTH is synthesized and secreted by the parathyroid gland and is the primary endocrine hormone that regulates systemic calcium and phosphorus homeostasis. The physiological effects of PTH include the release of calcium and phosphorus from bone; retention of calcium rather than phosphorus in the kidneys by increasing calcium reabsorption in the renal tubules but decreasing phosphate reabsorption in the renal tubules; and stimulating the renal production of active vitamin D (1,25(OH) ₂ vitamin D₃), which in turn enhances calcium and phosphorus absorption in the intestines. Without the renal action of PTH to store calcium and excrete phosphorus, conventional therapies using vitamin D analogs and calcium supplements can lead to renal insufficiency or failure due to progressive nephrocalcinosis, and if levels remain high for a long period, it can lead to ectopic calcification (ectopic calcification in the basal ganglia, lens of the eye, and vascular system) due to a chronic increase in calcium × phosphorus products that precipitate as calcium phosphate crystals. Recently, Natpara® PTH(1-84) was approved by the FDA for the treatment of hypoparathyroidism. For a long time, Forteo® PTH(1-34) has also been used for hypoparathyroidism, even though it is not approved for this indication, with injections administered once, twice, or three times daily. PTH acts as an anabolic agent on bone by preferentially activating osteoblasts over osteoclasts when delivered intermittently, for example, by daily or frequent injections of PTH(1-84) or PTH(1-34). This anabolic effect of intermittent exposure to PTH contrasts with the net bone catabolism that can occur with continuous exposure to PTH. The anabolic capacity of intermittent administration of PTH agonists has been well utilized in the treatment of osteoporosis, where bone turnover is usually high and bone mineral density (BMD) is low, whereas the opposite is true in hypoparathyroidism. The primary complication of hypoparathyroidism is hypercalciuria, resulting from a lack of PTH-dependent calcium reabsorption in the distal renal tubules. Hypercalciuria is associated with an increased risk of nephrocalcinosis, nephrolithiasis, and renal failure. According to the FDA review of Natpara, daily injections of PTH failed to provide adequate control of urinary calcium excretion due to the short half-life of this PTH agonist in the body. Furthermore, non-physiological PTH levels may be associated with hypercalcemia and hypocalcemia. Treatment with Natpara did not improve the incidence of these complications compared to placebo. This can be partly explained by the unfavorable pharmacokinetics of Natpara. For example, administration of the currently approved dose of Natpara results in levels of PTH well above the physiological level where the Cmax is 300 pg/ml, which returns to baseline at 12 hours. As a result, patients are overtreated in the initial stages after administration, and treatment insufficient during the period until the next dose. Hypocalcemia is accompanied by a wide range of symptoms, some of which can be fatal. These include tetany, paresthesia, cognitive impairment, loss of consciousness with seizures (grand mal seizures), renal dysfunction, cardiac arrhythmias and syncope, and even heart failure. Therefore, there is a significant unmet need for more physiological PTH treatments that allow for sustained exposure to PTH without causing hypercalcemia, enabling the alleviation of symptoms associated with hypocalcemia, hypercalciuria, and hyperphosphatemia. PTH replacement therapy becomes more physiological when delivered by continuous infusion, for example, using an insulin pump. This has been demonstrated, for example, by Winer et al. (J Pediatr, 2014, 165(3), 556-563), in their study, that pump del