KR-20260068094-A - PTH treatment for chronic kidney disease

Abstract

The present invention relates to a PTH compound and related aspects for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD or in the treatment of subjects suffering from CKD.

Inventors

• 마카라 마이클 앤서니
• 슈 에이미 디
• 시블리 크리스토퍼

Assignees

• 아센디스 파마 본 디지즈 에이/에스

Dates

Publication Date

20260513

Application Date

20240903

Priority Date

20230904

Claims (20)

1. PTH compound for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD or in the treatment of subjects suffering from CKD.
2. In paragraph 1, the PTH compound is a PTH compound used for the treatment of a subject suffering from CKD.
3. In paragraph 1, the PTH compound is a PTH compound used for the prevention of CKD in subjects at risk of developing CKD.
4. A PTH compound according to claim 1 or 3, wherein the renal function of a subject suffering from CKD is evaluated at least once by blood and/or urine tests prior to administration of a pharmaceutically effective dose of the PTH compound.
5. A PTH compound according to any one of claims 1 to 4, wherein the renal function of a subject at risk of developing CKD or suffering from CKD is evaluated at least twice by blood and/or urine tests, the first evaluation is performed before the first administration of the PTH compound, and the second evaluation is performed after the administration of one or more doses of the PTH compound.
6. In paragraph 5, a PTH compound in which the secondary evaluation is performed after the administration of multiple doses.
7. A PTH compound according to claim 5 or 6, wherein the secondary evaluation is performed after at least 2 weeks of treatment, after at least 4 weeks of treatment, after at least 2 months of treatment, or after at least 6 months of treatment.
8. A PTH compound according to any one of paragraphs 4 through 7, wherein the blood test measures the amount of creatinine in the blood.
9. A PTH compound according to any one of paragraphs 4 through 8, wherein the urine test measures the urine albumin-creatinine ratio (UCAR).
10. A PTH compound according to any one of paragraphs 4 through 9, wherein kidney function is measured in the form of an estimated glomerular filtration rate (eGFR).
11. In paragraph 10, the PTH compound in which eGFR is measured at least once prior to the administration of a pharmaceutically effective dose of the PTH compound.
12. In paragraph 10 or 11, the PTH compound in which eGFR is determined using the Dietary Modified Renal Disease (MDRD) formula.
13. In any one of paragraphs 10 to 12, eGFR is a PTH compound representing CKD.
14. In any one of claims 10 to 13, the subject is a PTH compound having an eGFR of < 60 ml/min/1.73 m².
15. A PTH compound in which the subject of any one of paragraphs 1 to 14 suffers from hypoparathyroidism.
16. A PTH compound in which the subject of any one of claims 1 to 15 suffers from chronic hypoparathyroidism.
17. In any one of paragraphs 1, 2 and 4 through 16, the treatment is a PTH compound that improves the eGFR of the subject.
18. A PTH compound according to any one of claims 1, 2 and 4 through 17, wherein treatment with the PTH compound causes an average improvement in the eGFR of a subject of at least 5 ml/min/1.73 m².
19. A PTH compound according to any one of claims 1, 2 and 4 through 18, wherein treatment with the PTH compound causes an average improvement in the eGFR of the subject of at least 6 ml/min/1.73 m².
20. A PTH compound according to any one of claims 1, 2 and 4 through 19, wherein treatment with the PTH compound causes an average improvement in the eGFR of the subject of at least 7 ml/min/1.73 m².

Description

PTH treatment for chronic kidney disease The present invention relates to a PTH compound and related aspects for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD or in the treatment of subjects suffering from CKD. Chronic hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, and a deficiency or insufficient production of parathyroid hormone (PTH). In the event of PTH deficiency, the mechanisms regulating calcium transport and phosphate reabsorption in the renal tubules, which are rich in PTH receptors, are disrupted, thereby impairing the kidney's primary role in regulating calcium and phosphate homeostasis. The risk of renal complications increases in patients with chronic hypoparathyroidism managed by conventional therapy consisting of oral calcium and active vitamin D. Patients with chronic hypoparathyroidism have a higher risk of developing chronic kidney disease (CKD), progression of CKD stages, and progression to end-stage renal failure (ESKD) compared to patients without the condition, and have been shown to experience a faster decline in estimated glomerular filtration rate (eGFR). Therefore, patients with hypoparathyroidism being treated with conventional therapies require close monitoring for hypoparathyroid symptoms and comorbidities, including the development of chronic kidney disease, the risk of kidney stones, and renal calcification. Although there is a growing number of studies showing an increased risk of renal complications in patients with chronic hypoparathyroidism, the underlying mechanism of this risk in the pathophysiology of hypoparathyroidism has not yet been elucidated. Chronic hypoparathyroidism is generally managed with conventional treatments aimed at maintaining serum calcium levels in the lower part of the normal range (i.e., 8.0-8.5 mg/dL; Adv Ther (2021) 38:1876-1888 1885). Chen et al. (J Clin Endocrinol Metab. 2020; 105: e3557-65) recently reported in a study of patients with chronic hypoparathyroidism that patients not treated with recombinant human PTH 1-84 (Natpara®) showed a decrease in eGFR of 8.0 ml/min/1.73 m² over a 5-year follow-up period. In contrast, patients treated with rhPTH 1-84 showed stable or minimal improvement in eGFR, suggesting that hormone replacement therapy can mitigate the decrease in eGFR. Compared to patients without hypoparathyroidism, patients with chronic hypoparathyroidism have a significantly increased risk of developing new CKD stage 3 or higher. Patients with chronic hypoparathyroidism have a significantly increased risk of progression to higher CKD stages and progression to ESKD compared to patients without hypoparathyroidism (Adv Ther (2021) 38:1876-1888 1885). Therefore, more effective treatments are needed for patients with chronic kidney disease, particularly those with hypoparathyroidism. The present application aims to resolve the above problems at least partially. The above objective is achieved with a PTH compound for use in the prevention of chronic kidney disease (CKD) in subjects at risk of developing CKD or in the treatment of subjects suffering from CKD. Surprisingly, when PTH compounds, such as those causing receptor signaling that is at least 10 times longer than PTH 1-84, were administered to subjects with CKD, particularly those with hypoparathyroidism and CKD with an eGFR of less than 60 ml/min/1.73 m², eGFR was found to improve continuously, whereas similar subjects who received conventional treatment experienced a decrease in eGFR. In this invention, terms having the following meanings are used. As used herein, with respect to serum calcium (sCa), the terms “within normal values” and “within normal range” refer to calcium levels generally observed in subjects of a specific species, sex, and age. In humans, normal serum calcium levels generally correspond to serum calcium levels in the range of 8.3 mg/dL (albumin-corrected) to 10.6 mg/dL (albumin-corrected). With respect to serum calcium levels, the term “albumin-corrected” means that the measured serum calcium level has been corrected to account for calcium bound to albumin according to the following formula: Albumin-corrected serum calcium (mg/dL) = Measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]). When serum calcium levels are within the normal range, it is also referred to as "normal calciumemia." As used herein, the term "initial dose" refers to the dose of the PTH compound administered to a subject when treatment with the PTH compound is first initiated, that is, the subject has not previously received a dose of the PTH compound. It is understood that the subject may maintain this initial dose for a certain period, e.g., several days, weeks, or months, or for the entire duration of treatment, or may increase or decrease the dose depending on specific circumstances, such as the occurrence of hypocalcemia or hypercalcemia. As used herein, the term "average" refers to t