Methods for controlling progression of hyperparathyroidism with calcifediol and compositions for use therein

Abstract

To provide methods and compositions for regulating hyperparathyroidism.SOLUTION: One aspect of the disclosure is a method for preventing, halting or reversing the SHPT progression in a subject, e.g., a human adult, defined as an increase in iPTH by >10% from the pretreatment baseline, the method comprising effective administration of 25-hydroxyvitamin D to increase and maintain serum total 25-hydroxyvitamin D in the patient to a concentration greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL or at least 60 ng / mL, and thereby preventing, halting, or reversing SHPT progression in the patient.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 802,148, filed February 6, 2019, is hereby claimed, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The present disclosure relates generally to the treatment of patients with elevated serum intact parathyroid hormone, e.g., patients with hyperparathyroidism. The present disclosure also relates to the treatment of SHPT, e.g., chronic kidney disease, and to controlling the progression of SHPT in chronic kidney disease (CKD).

[0003] A brief description of related technologies SHPT is a disorder that develops primarily due to vitamin D insufficiency (VDI) and deficiency. It is characterized by abnormally high blood levels of parathyroid hormone (PTH) and, in the absence of early detection and treatment, becomes associated with parathyroid hyperplasia and a series of metabolic bone diseases. It is a common complication of CKD, with an increasing incidence as the disease progresses. SHPT can also develop in individuals with healthy kidneys due to environmental, cultural, or dietary factors that prevent adequate vitamin D supply.

[0004] With regard to SHPT and its occurrence in CKD, there is a progressive loss of cells in the proximal nephron, which is the primary site of synthesis of vitamin D hormone (collectively, "1,25-dihydroxyvitamin D") from 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. In addition, loss of functioning nephrons results in the retention of excess phosphorus and reduced activity of renal 25-hydroxyvitamin D-1α-hydroxylase, the enzyme that catalyzes the reaction that produces the D hormone. These two events explain the low serum levels of 1,25-dihydroxyvitamin D commonly seen in patients with moderate to severe CKD when vitamin D supply is adequate.

[0005] CKD is characterized by overproduction of intact parathyroid hormone (iPTH) and hypertrophy of the parathyroid glands. This is associated with decreased serum total 25-hydroxyvitamin D, elevated serum phosphorus and fibroblast growth factor 23 (FGF23), and decreased serum 1,25-dihydroxyvitamin D and calcium. Untreated SHPT can lead to bone disease, increased fracture rates, increased vascular calcification, and increased morbidity and mortality. Decreased serum levels of 1,25-dihydroxyvitamin D increase the secretion of PTH by direct and indirect mechanisms, eventually leading to excess. The resulting hyperparathyroidism leads to a marked increase in bone turnover and its sequelae, renal osteodystrophy, which may include osteitis fibrosa cysticum, osteomalacia, osteoporosis, extraskeletal calcification, and various other disorders, such as bone pain, periarthritis, and Mockerberg's sclerosis. Decreased serum levels of 1,25-dihydroxyvitamin D can also cause growth retardation with muscle weakness and skeletal deformities (most often seen in pediatric patients).

[0006] Vitamin D compounds have traditionally been administered in immediate release formulations. Formulations for delivering active vitamin D, its analogs, and its prohormones have been disclosed, including several sustained release dosage forms. For example, several modified release dosage forms of vitamin D compounds, in wax matrix form, have been described. One such formulation is sold under the trade name RAYALDEE® (calcifediol), a product approved for treating SHPT in patients with stage 3 and 4 chronic kidney disease (CKD). The prescribing information for this drug indicates that the sustained release formulation of RAYALDEE® is a wax-based sustained release formulation of 25-hydroxyvitamin D3. See U.S. Patent Application Publication Nos. US2009 / 311316A1 (December 17, 2009), US2009 / 0176748A1 (July 9, 2009), US2013 / 0137663A1 (May 30, 2013), US2014 / 0349979A1 (November 27, 2014), WO2017 / 182237A1 (October 26, 2017), and U.S. Patent Application No. 62 / 725940 (filed August 31, 2018), the disclosures of which are incorporated herein by reference in their entireties.

[0007] Clinical practice guidelines target vitamin D sufficiency. However, there is a lack of consensus on the definition of vitamin D sufficiency in CKD. In 2003, the National Kidney Foundation (NKF) defined vitamin D sufficiency as a serum total 25-hydroxyvitamin D concentration greater than 30 ng / mL, and in 2011, the Endocrine Society defined it as a concentration between 30 and 100 ng / mL. The United States (US) Institute of Medicine (IOM) disagreed, stating in 2011 that "virtually all individuals have sufficient serum 25-hydroxyvitamin D levels of at least 20 ng / mL." The results described herein indicate that higher levels are needed to control the rise in serum iPTH as CKD progresses and to control the progression of hyperparathyroidism. Summary of the Invention

[0008] One aspect of the disclosure provides a method of preventing, halting, or reversing SHPT progression in a subject, e.g., an adult human, defined as a >10% increase in iPTH from a pre-treatment baseline, wherein effective administration of 25-hydroxyvitamin D increases and maintains the subject's serum total 25-hydroxyvitamin D to a concentration of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, or at least 60 ng / mL, thereby preventing, halting, or reversing SHPT progression in the patient.

[0009] Another aspect of the disclosure provides a method of preventing, halting, or reversing SHPT progression in a patient population, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising effectively administering 25-hydroxyvitamin D to increase and maintain a patient's serum total 25-hydroxyvitamin D to an average concentration of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL or at least 60 ng / mL, thereby preventing, halting, or reversing SHPT progression in the patient population, wherein the percentage of subjects experiencing SHPT progression is less than 30%, 25%, 20%, 15%, 10%, or 9.7% or less, or less than 3%, or 2.8% or less.

[0010] A further embodiment of the present disclosure is a method of preventing, halting, or reversing SHPT progression in a patient, defined as a >10% increase in plasma iPTH from pre-treatment baseline, comprising: (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to a degree greater than that achieved with vitamin D analogs (VDA) or nutritional vitamin D (NVD), hydroferol, or a combination thereof; (b) decreasing the patient's serum iPTH; or (c) any combination thereof. Optionally, the method comprises: (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to a degree at least twice that achieved with VDA, NVD, hydroferol, or any combination thereof; (b) decreasing the patient's serum iPTH; or (c) any combination thereof. In various embodiments, serum total 25-hydroxyvitamin D is increased by more than 20 ng / mL compared to pre-treatment levels. In various embodiments, serum iPTH is reduced by at least 10 pg / mL, at least 20 pg / mL, or at least 30 pg / mL compared to pre-treatment levels. In various examples, serum iPTH is reduced by more than 30% compared to pre-treatment levels.

[0011] Further, an embodiment of the present disclosure is a method of preventing, halting, or reversing SHPT progression in a patient, defined as a >10% increase in plasma iPTH from a pre-treatment baseline, comprising: (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D by more than 20 ng / mL compared to pre-treatment levels; (b) decreasing the patient's serum iPTH by at least 30% compared to pre-treatment levels; or (c) a combination thereof. In various examples of the presently disclosed methods of preventing, halting, or reversing SHPT progression, prevention, halting, or reversal of SHPT progression is achieved for 26 weeks or more.

[0012] Another aspect of the disclosure is a method of treating a disease, condition, or disorder associated with an increase in iPTH from the patient's baseline in a patient in need of such treatment, comprising administering 25-hydroxyvitamin D effectively to increase and maintain the patient's serum total 25-hydroxyvitamin D in the range of about 50 to about 300 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, optionally about 60 ng / mL to about 300 ng / mL during chronic administration, thereby treating the disease, condition, or disorder.

[0013] Another aspect of the present disclosure is a method of reducing SHPT progression in a patient in need of treatment, comprising administering 25-hydroxyvitamin D at a dosage in the range of 100-900 μg per week to effectively gradually increase and thereafter maintain the patient's serum total 25-hydroxyvitamin D level to a concentration in the range of about 50-300 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, optionally between about 60 ng / mL and about 300 ng / mL, thereby reducing the progression of SHPT progression in the patient.

[0014] Another embodiment of the present disclosure is a method of treating a patient by (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to greater than 20 ng / mL, (b) decreasing the patient's serum iPTH to at least 30 pg / mL, or (c) any combination thereof, the method comprising administering to the patient an amount of 25-hydroxyvitamin D for a treatment period of at least six months. In various examples of any one of the disclosed methods, serum calcium and phosphorus levels do not change in the patient during the treatment period.

[0015] Another embodiment of the disclosure is a method of treating SHPT in a patient with CKD, comprising administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration, or based on the patient's weight and a desired increase in serum 25-hydroxyvitamin D. In various embodiments, the method comprises selecting a dose for the patient to provide a post-treatment serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml. In various examples, the method comprises selecting a dose for the patient to provide a steady-state serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml. Optionally, administration is by sustained release oral administration. In various embodiments, the dose is a daily dose. In various embodiments, the dose (D) in mcg is a daily dose or equivalent daily dose selected according to the relationship D=(RxW) / F as a function of the patient's weight at the start of therapy in kilograms (W) and the desired increase in serum 25-hydroxyvitamin D in ng / ml (R), including a scaling factor (F), where F is in the range of about 60 to about 80, or about 65 to about 75, or about 68 to about 72, or about 69 to about 71, or about 70. In various cases, the patient's weight W is in the range of 50 kg to 180 kg. The patient, in some embodiments, has stage 3 or stage 4 CKD. Also, in various embodiments, the patient's dose is selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration to provide a post-treatment serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml. In an illustrative example, the method further provides for at least a 30% decrease in the patient's plasma iPTH concentration compared to a pre-treatment baseline.

[0016] Another aspect of the disclosure is a pharmaceutical composition for use in the methods described herein, e.g., a pharmaceutical composition comprising 25-hydroxyvitamin D and a pharma- ceutically acceptable excipient, wherein the composition is administered to treat a disease or condition associated with an increase in iPTH from baseline, wherein the administration increases and maintains serum levels of 25-hydroxyvitamin D in the range of about 50 to about 300 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, optionally between about 60 ng / mL and about 300 ng / mL during chronic administration of the composition.

[0017] In various examples of any one of the disclosed methods, the method includes increasing 25-hydroxyvitamin D to maintain the patient's serum total 25-hydroxyvitamin D level at a concentration in the range of greater than 50 ng / mL to about 300 ng / mL, optionally about 60 ng / mL to about 300 ng / mL, or greater than 50 ng / mL to about 200 ng / mL, optionally about 60 ng / mL to about 200 ng / mL, or greater than 50 ng / mL to about 100 ng / mL, optionally about 60 ng / mL to about 100 ng / mL, optionally for a period of at least 8 weeks, or at least 10 weeks, or at least 12 weeks, or at least 14 weeks. In various embodiments, administering 25-hydroxyvitamin D includes avoiding a significant increase in the patient's corrected serum calcium level, serum phosphorus level, serum FGF23 level, or any combination thereof, compared to a pre-treatment baseline.

[0018] In various embodiments, the patient has greater than or about 30 ng / mL of serum total 25-hydroxyvitamin D at the start of therapy. Optionally, the patient has greater than or about 40 ng / mL of serum total 25-hydroxyvitamin D at the start of therapy.

[0019] In various embodiments of any one of the methods of the present disclosure, the method includes administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight at the start of therapy. In various cases, the dose is or corresponds to a daily dose of about 0.1 mcg / kg of the patient's weight at the start of therapy to about 1 mcg / kg of the patient's weight at the start of therapy, optionally an amount that is or corresponds to a daily dose of about 0.15 mcg / kg of the patient's weight at the start of therapy to about 0.85 mcg / kg of the patient's weight at the start of therapy. In exemplary embodiments, the daily dose is about 0.4 mcg / kg to about 0.8 mcg / kg of the patient's weight at the start of therapy. For example, the method includes administering to the patient a starting dose of 60 mcg if the patient's weight at the start is 140 kg or more.

[0020] In various embodiments of any one of the methods of the present disclosure, SHPT progression (and lack thereof) is based on 26 weeks or more of treatment compared to (a) untreated patients, or (b) patients treated with active vitamin D therapy (optionally calcitriol, paricalcitol, or doxercalciferol), (c) patients treated with nutritional vitamin D (ergocalciferol and / or cholecalciferol), or (d) patients treated with hydroferol.

[0021] The subject may be a subject who is vitamin D deficient at the start of therapy, e.g., has a serum total 25-hydroxyvitamin D of less than 30 ng / mL. The amount of 25-hydroxyvitamin D administered may be effective to achieve a patient's or population's average serum total 25-hydroxyvitamin D level of up to about 93 ng / mL, or up to 92.5 ng / mL, or up to about 90 ng / mL, or up to about 85 ng / mL, or up to about 80 ng / mL, or up to about 70 ng / mL, or up to about 69 ng / mL, or up to 68.9 ng / mL. The subject may include those with CKD stages 3-5, or stages 3-4, or stage 5. The administered 25-hydroxyvitamin D may comprise, consist essentially of, or consist of 25-hydroxyvitamin D3, also known as calcifediol. The 25-hydroxyvitamin D may be administered in a modified release form, including sustained release (also known as extended or sustained release). Administration can be by any suitable route, for example, orally, intravenously, or transdermally. 25-hydroxyvitamin D can also be administered intravenously over an extended period of time, for example, over a period of at least 1 hour, optionally up to 5 hours, for example, via gradual injection or infusion. The route and / or schedule of administration can be such that substantial induction of CYP24A1 is avoided, for example, characterized by a VMR of 5 or less or 4.8 or less. The dose of 25-hydroxyvitamin D can be provided, for example, twice a week, three times a week, or once a week, for example, daily, or on another episodic basis. As described above, the dosage is effective to increase and maintain the subject's serum total 25-hydroxyvitamin D to a concentration of more than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, for example, 30 μg per day, or 60 μg per day, or 90 μg per day. The 25-hydroxyvitamin D can be administered in a unit dosage form containing between 30 μg and 1000 μg of 25-hydroxyvitamin D, or between 30 μg and 600 μg of 25-hydroxyvitamin D, for example 30 μg, or 60 μg, or 90 μg, or 200 μg.In some embodiments, the methods include administering 25-hydroxyvitamin D in the range of about 100 μg to about 900 μg per week, or in the range of about 300 μg to about 900 μg per week, e.g., 600 μg per week, optionally divided into two or three doses per week, e.g., administered three times per week during dialysis treatment.

[0022] For the methods, articles and kits described herein, it is contemplated that optional features, including but not limited to components, compositional ranges thereof, alternatives, conditions, and steps, are selected from the various aspects, embodiments, and examples provided herein.

[0023] Further aspects and advantages will be apparent to those skilled in the art from a consideration of the following detailed description. While the method is susceptible to embodiment in various forms, the following description includes specific embodiments with the understanding that such disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. [Brief description of the drawings]

[0024] To facilitate a better understanding of the invention, three drawings are attached hereto.

[0025] [Figure 1-1]Changes in serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and plasma iPTH by treatment group and CKD stage are shown. Mean (SE) data for PP subjects at pretreatment baseline (week 0), weeks 8-12, and weeks 20-26 were analyzed by treatment group and CKD stage. Differences between active and corresponding placebo groups or between CKD stages were calculated by t-test. Figure 1(A) shows serum total 25-hydroxyvitamin D (25-OH-D). Figure 1(B) shows serum total 1,25-dihydroxyvitamin D (1,25(OH)2D). Figure 1(C) shows plasma iPTH. ¶ indicates significant difference from corresponding placebo group, p<0.05; ¶¶ indicates significant difference from corresponding placebo group, p<0.01; ¶¶¶¶ indicates significant difference from corresponding placebo group, p<0.0001. In each of Figures 1(A) to 1(C), bar graphs are shown in the following order from left to right for each group: placebo-CKD3, placebo-CK4, ER-CKD3, and ER-CKD4. [Figure 1-2] Table 2 [Figure 1-3] Table 3 [Diagram 2] Analysis of plasma iPTH by quintile of 25-hydroxyvitamin D during and after treatment is shown. Mean (SE) data from PP subjects were analyzed within given quintiles (top of Fig. 2A and Fig. 2B) by treatment period [baseline (week 0), week 12 (mean of weeks 8–12 of treatment) and EAP (efficacy evaluation period, mean of weeks 20–26 of treatment), Fig. 2(A)], and by post-25-hydroxyvitamin D treatment quintile (n=71–72, respectively) (bottom of Fig. 2B). Differences from baseline (shown in Fig. 2A) and quintile 1 at EAP (shown in Fig. 2B) were calculated by ANOVA followed by Bonferroni correction. ULN=upper limit of normal. * indicates significant difference from baseline, p<0.05; ** indicates significant difference from baseline, p<0.01; **** indicates significant difference from baseline, p<0.0001; ††† indicates significant difference from quintile 1, p<0.0001. [Diagram 3]Analysis of plasma iPTH response rates by post-treatment 25-hydroxyvitamin D quintile. The proportion of per-protocol (PP) subjects achieving an iPTH response, defined as a mean ≥ 30% decrease in plasma iPTH from pre-treatment baseline, was analyzed as a function of mean, post-treatment serum total 25-hydroxyvitamin D quintile. ††† indicates significant difference from quintile 1, p<0.05. [Figure 4] The distribution of patients among the study cohorts is shown in relation to Example 2 below. [Diagram 5] With reference to Example 1 below, the relationship between patient weight and dose-response in serum 25-hydroxyvitamin D levels after 12 weeks of treatment with 30 mcg ERC per day is shown. [Figure 6] With reference to Example 1 below, the relationship between patient weight and dose-response in serum 25-hydroxyvitamin D levels after 12 weeks of treatment with 30 mcg ERC per day is shown. [Figure 7] With reference to Example 1 below, the relationship between patient weight and dose-response in serum 25-hydroxyvitamin D levels after 12 weeks of treatment with 30 mcg ERC per day is shown. [Figure 8] With reference to Example 1 below, the relationship between patient weight and dose-response in serum 25-hydroxyvitamin D levels after 12 weeks of treatment with 30 mcg ERC per day is shown. [Figure 9] Table 6 [Figure 10] Table 7 [Figure 11] Table 9 [Figure 12] Table 10 [Figure 13] Table 10 continued DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Described herein are materials and methods for preventing, reducing, halting, or reversing SHPT progression, materials and methods for treating diseases, conditions, or disorders associated with an increase in iPTH from baseline, and related compositions for such methods and uses.

[0027] The results described herein show that increasing mean serum total 25-hydroxyvitamin D to a level of 92.5 ng / mL over 26 weeks in CKD stage 3 and 4 patients with extended-release calcifediol (ERC) did not adversely affect mean serum calcium, phosphorus, FGF23, eGFR, VMR, or urinary Ca:Cr ratio, and did not increase mean serum 1,25-dihydroxyvitamin D above the upper limit of normal (ULN, 62 pg / mL). Extending these studies to 52 weeks of ERC treatment did not result in increased risk associated with these parameters. A positive correlation was observed between serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, but no correlation was observed between serum total 25-hydroxyvitamin D and serum calcium or phosphorus.

[0028] Achieving mean serum total 25-hydroxyvitamin D levels of at least 50.8 ng / mL, and these levels as described herein, is associated with proportional increases in serum 1,25-hydroxyvitamin D and decreases in plasma iPTH and serum bone turnover markers, attenuating SHPT progression defined as a >10% increase in EOT iPTH from pre-treatment baseline, and is not associated with adverse changes in mean serum calcium, phosphorus, FGF23, eGFR, or urinary Ca:Cr ratio.

[0029] The increased 25-hydroxyvitamin D exposure described herein also not only attenuates the progressive rise in serum bone turnover markers, but actually reduces the levels of these markers, suggesting improved control of high-turnover bone disease and reduced risk of associated adverse sequelae. Bone deterioration and resulting fractures are important causes of morbidity and mortality in CKD patients with SHPT. Even modestly elevated PTH has recently been demonstrated to cause profound changes in bone structure and reduce spinal BMD. Poor bone health is strongly associated with vascular calcification and associated high rates of cardiovascular morbidity and mortality in CKD, and there has been great interest in diagnosing and correcting bone disease in kidney disease patients to improve bone health and reduce health care costs.

[0030] Another embodiment of the methods herein normalizes plasma iPTH in, for example, stage 3 or 4 or 5 CKD patients with SHPT by increasing the patient's serum total 25-hydroxyvitamin D to levels greater than 92.5 ng / mL, e.g., at least 95 ng / mL, or at least 100 ng / mL, or at least 125 ng / mL, or at least 150 ng / mL, at least 175 ng / mL, at least 200 ng / mL, by the methods described herein, without disrupting calcium metabolism, or phosphorus metabolism, or markers of these, or any combination of the foregoing. The methods may include, for example, repeated administration to achieve serum 25-D levels in the range of about 120 ng / mL to about 200 ng / mL, or about 120 ng / mL to about 160 ng / mL, or about 150 ng / mL to about 200 ng / mL.

[0031] The materials and methods are intended to include embodiments that include any combination of one or more of the optional additional elements, features, and steps detailed below, unless otherwise stated.

[0032] In jurisdictions that prohibit patents on methods performed on the human body, the meaning of "administering" a composition to a human subject shall be limited to formulating a prepared substance that the human subject would self-administer in any manner (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with any statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patents on methods performed on the human body, "administering" a composition includes both methods performed on the human body and the aforementioned activities.

[0033] As used herein, the term "comprising" indicates the possibility of including other agents, elements, steps or features in addition to those specified.

[0034] As used herein, "vitamin D insufficiency and deficiency" is generally defined as a total serum 25-hydroxyvitamin D level below 30 ng / mL.

[0035] As used herein, "hypercalcemia" refers to the condition in a patient in which the patient has a corrected serum calcium level greater than 10.2 mg / dL. The normal corrected serum calcium level in humans is approximately 8.6-10.2 mg / dL. As used herein, the term "hypercalciuria" refers to the condition in a patient in which the patient has a urinary calcium excretion greater than 275 mg in men and greater than 250 mg in women. In an alternative, hypercalciuria can be defined as a daily urinary excretion of calcium greater than 4 mg per kg of body weight. As another alternative, hypercalciuria can be defined as a 24-hour urinary calcium concentration greater than 200 mg of calcium per liter of urine.

[0036] As used herein, the term "hyperphosphatemia" refers to the condition in a patient where the serum phosphorus level is greater than 4.6 mg / dL.

[0037] As used herein, the term 25-hydroxyvitamin D generally refers to forms of 25-hydroxyvitamin D, including 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, and 25-hydroxyvitamin D4. In any of the methods described herein, it is contemplated that the use of 25-hydroxyvitamin D may comprise, consist of, or consist essentially of a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3. In any of the methods described herein, it is contemplated that the use of 25-hydroxyvitamin D may comprise, consist of, or consist essentially of 25-hydroxyvitamin D3.

[0038] As used herein, the term "total serum 25-hydroxyvitamin D" refers to the sum of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in serum.

[0039] As used herein, the term 1,25-dihydroxyvitamin D generally refers to forms of 25-hydroxyvitamin D, including 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3. The term "serum total 1,25-dihydroxyvitamin D" refers to the sum of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in serum.

[0040] In any method or use according to the present disclosure, effective administration of 25-hydroxyvitamin D may include, for example, administration in an amount of 30-150 μg on average per day. For example, daily doses may be 30 μg, 60 μg, 90 μg, or 120 μg. Individual doses may range, for example, from 5 to 1,000 μg.

[0041] 25-hydroxyvitamin D can be administered on any suitable schedule. For example, the dosing schedule can be, for example, daily, or less frequently, or every other day, or twice a week, or three times a week, or weekly, or every other week. Effective administration can include administering 25-hydroxyvitamin D in the range of about 100 μg to about 900 μg per week, or in the range of about 300 μg to about 900 μg per week, optionally 600 μg per week. The weekly dose can be divided, for example, into two or three doses per week. For example, the dose can be administered three times a week during dialysis treatment.

[0042] 25-hydroxyvitamin D can be administered with or without food, or independently of food. In certain embodiments, 25-hydroxyvitamin D is administered without food, for example, at bedtime, to reduce the variability of 25-hydroxyvitamin D absorption with food.

[0043] In any method or use according to the present disclosure, the method comprises administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight at the start of therapy, and optionally based on the patient's serum 25-hydroxyvitamin D level at the start of therapy and / or the desired increase in the patient's serum 25-hydroxyvitamin D as a result of the treatment. In various embodiments, the dose is or corresponds to a daily dose of about 0.1 mcg / kg of the patient's weight at the start of therapy to about 1 mcg / kg of the patient's weight at the start of therapy, optionally from about 0.15 mcg / kg of the patient's weight at the start of therapy to about 0.85 mcg / kg of the patient's weight at the start of therapy. In some embodiments, the daily dose is about 0.4 mcg / kg to about 0.8 mcg / kg of the patient's weight at the start of therapy, and optionally the method comprises administering to the patient a starting dose of 60 mcg if the patient's weight at the start is 140 kg or more.

[0044] Another embodiment of the disclosure is a method of treating SHPT in a patient with CKD, comprising administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration, or based on the patient's weight and a desired increase in serum 25-hydroxyvitamin D. In various embodiments, the method comprises selecting a dose for the patient to provide a post-treatment serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml. In various examples, the method comprises selecting a dose for the patient to provide a steady-state serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml. Optionally, administration is by sustained release oral administration. In various embodiments, the dose is a daily dose. In various embodiments, the dose (D) in mcg is a daily dose or equivalent daily dose selected according to the relationship D=(RxW) / F as a function of the patient's weight at the start of therapy in kilograms (W) and the desired increase in serum 25-hydroxyvitamin D in ng / ml (R), including a scaling factor (F), where F is in the range of about 60 to about 80, or about 65 to about 75, or about 68 to about 72, or about 69 to about 71, or about 70. In various cases, the patient's weight W is in the range of 50 kg to 180 kg. The patient, in some embodiments, has stage 3 or stage 4 CKD. Also, in various embodiments, the patient's dose is selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration to provide a post-treatment serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml. In an illustrative example, the method further provides for at least a 30% decrease in the patient's plasma iPTH concentration compared to a pre-treatment baseline.

[0045] In any method or use according to the present disclosure, the effective administration of 25-hydroxyvitamin D may include administering 25-hydroxyvitamin D to increase serum total 25-hydroxyvitamin D to a level of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL or at least 60 ng / mL. From a population perspective, the percentage of subjects experiencing SHPT progression may be, for example, less than 30%, 25%, 20%, 15%, 10%, or 9.7% or less, or less than 3%, or 2.8% or less. The amount of 25-hydroxyvitamin D administered is effective to achieve a patient or population mean total serum 25-hydroxyvitamin D level of up to 300 ng / mL, or up to 200 ng / mL, or up to 150 ng / mL, or up to 120 ng / mL, or up to 100 ng / mL, or up to about 93 ng / mL, or up to 92.5 ng / mL, or up to about 90 ng / mL, or up to about 85 ng / mL, or up to about 80 ng / mL, or up to about 70 ng / mL, or up to about 69 ng / mL, or up to 68.9 ng / mL, without causing hypercalcemia, hyperphosphatemia, and / or hypercalciuria. For example, the method can include increasing 25-hydroxyvitamin D to maintain the patient's serum total 25-hydroxyvitamin D level at a concentration in the range of greater than 50 ng / mL to about 300 ng / mL, or greater than 50 ng / mL to about 200 ng / mL, or greater than 50 ng / mL to about 100 ng / mL, optionally in the range of 60 ng / mL to about 300 ng / mL, or greater than 60 ng / mL to about 200 ng / mL, or greater than 60 ng / mL to about 100 ng / mL. The method can include 25-hydroxyvitamin D therapy that increases serum total 25-hydroxyvitamin D to such levels and / or amounts for at least 12 weeks, at least 19 weeks, or at least 26 weeks after initiation of 25-hydroxyvitamin therapy, and can be continued for any desired period of time, e.g., at least 39 weeks, or at least 52 weeks or more. In various embodiments, prevention, halting, or reversal of SHPT progression is achieved for 26 weeks or more.The method can include 25-hydroxyvitamin D therapy to increase serum total 25-hydroxyvitamin D to a level and / or, e.g., an amount that maintains a steady-state serum total 25-hydroxyvitamin D level in a therapeutic target range, e.g., in such a range.

[0046] In various embodiments, SHPT progression is based on 26 weeks of treatment compared to (a) untreated patients, or (b) patients treated with active vitamin D therapy (optionally calcitriol, paricalcitol, or doxercalciferol), (c) patients treated with nutritional vitamin D (ergocalciferol and / or cholecalciferol), or (d) patients treated with hydroferol. For example, a comparison of SHPT progression after 26 weeks of treatment can be made with patients receiving 1 mcg of paricalcitol daily, or patients receiving 0.25 μg of calcitriol per day, or patients receiving 0.5 μg of calcitriol per day, or patients receiving 0.25 μg of doxercalciferol per day, or patients receiving ergocalciferol (14,000 IU per day, or 35,000 IU per day, or 50,000 IU per day, or 105,000 IU per day), or patients receiving cholecalciferol (5,000 IU per day, or 7,000 IU per day, or 14,000 IU per day, or 28,000 IU per day, or 35,000 IU per day, or 50,000 IU per day). Also provided is a method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pretreatment baseline, comprising (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to a degree greater than that achieved with vitamin D analogs (VDA) or nutritional vitamin D (NVD), hydroferol, or any combination thereof, (b) decreasing the patient's serum iPTH, or (c) any combination thereof. Optionally, the method comprises (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to a degree at least twice that achieved with VDA, NVD, hydroferol, or any combination thereof, (b) decreasing the patient's serum iPTH, or (c) any combination thereof. In various embodiments, serum total 25-hydroxyvitamin D is increased by more than 20 ng / mL compared to pretreatment levels.In various embodiments, serum iPTH is reduced by at least 10 pg / mL, at least 20 pg / mL, or at least 30 pg / mL compared to pre-treatment levels. In various examples, serum iPTH is reduced by more than 30% compared to pre-treatment levels.

[0047] Further provided are methods of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising: (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D by more than 20 ng / mL compared to pre-treatment levels; (b) decreasing the patient's serum iPTH by at least 30% compared to pre-treatment levels; or (c) a combination thereof. In various examples of the disclosed methods of preventing, halting, or reversing SHPT progression, prevention, halting, or reversal of SHPT progression is achieved for 26 weeks or more.

[0048] Further provided is a method of treating a patient by (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D at or above 20 ng / mL, (b) decreasing the patient's serum iPTH by at least 30 pg / mL, or (c) any combination thereof, the method comprising administering to the patient an amount of 25-hydroxyvitamin D for a treatment period of at least six months.

[0049] Another aspect of the disclosure is a method of treating a patient with SHPT and CKD (e.g., stage 3 or stage 4) with a dose of 25-hydroxyvitamin D (e.g., 25 hydroxyvitamin D3) selected based on the patient's weight to provide a desired increase (elevation) in the patient's serum 25-hydroxyvitamin D levels. Additionally or alternatively, there are methods of treating a patient with SHPT and CKD (e.g., stage 3 or stage 4) with a dose of 25-hydroxyvitamin D (e.g., 25 hydroxyvitamin D3) selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration before treatment to provide a desired serum 25-hydroxyvitamin D level, e.g., after treatment or at steady state.

[0050] It was observed that after 12 weeks of daily administration of 30 mcg of Rayaldee® sustained-release calcifediol, patients who were underweight at the start of therapy experienced a greater increase in serum 25-hydroxyvitamin D, while patients who were overweight at the start of therapy experienced a smaller increase in serum 25-hydroxyvitamin D (see FIG. 5 in Example 1 below). Patient serum 25-hydroxyvitamin D concentrations obtained after 12 weeks of therapy also tended to be at higher levels in patients with lower body weights, although the levels were also influenced by the patient's baseline serum 25-hydroxyvitamin D concentration (see FIG. 6 in Example 1 below). In other words, patients with higher body weights require higher doses of 25-hydroxyvitamin D to experience a comparable increase in serum 25-hydroxyvitamin D. Similarly, for an overweight patient with insufficient or deficient vitamin D (e.g., baseline serum 25-hydroxyvitamin D of 10 ng / ml), a relatively high dose is required for the patient to reach a serum 25-hydroxyvitamin D level of 50 ng / ml, and an even higher dose is required for the patient to experience at least a 30% drop in plasma iPTH. It was also observed that a patient's increase in serum 25-hydroxyvitamin D concentration (ng / ml) as a function of dose (30 mcg) per baseline body weight (kg) showed a positive correlation, e.g., when fitted to a linear model, the slope was about 63 and when the intercept was adjusted to zero, it was about 70 (see FIG. 7 in Example 1 below).

[0051] In view of the above, provided herein is a method of treating hyperparathyroidism (e.g., SHPT) in a patient (e.g., a patient with CKD), comprising administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration, or based on the patient's weight and a desired increase in serum 25-hydroxyvitamin D. Also provided is a method of treating any condition that would benefit from an increase in serum 25-hydroxyvitamin D concentration (e.g., vitamin D deficiency), comprising administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration, or based on the patient's weight and a desired increase in serum 25-hydroxyvitamin D. The dose can be selected to provide any desired increase in serum 25-hydroxyvitamin D concentration (e.g., at least 10 ng / ml, or 20 ng / ml, or 30 ng / ml, or 40 ng / ml, or 45 ng / ml, or 50 ng / ml) or any post-treatment (or steady-state) serum 25-hydroxyvitamin D concentration (e.g., at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml). Administration can be in any suitable form and route of administration, e.g., sustained release administration by any route, oral administration by any release mechanism, and is also contemplated as sustained release oral administration. The frequency of administration can be selected as needed, e.g., daily, every other day, three times per week, weekly, every other week, or monthly. Daily administration by sustained release oral administration is contemplated. If a frequency other than daily dosing is chosen, the dose can simply be scaled (ratioed) based on the equivalent daily administration strength, e.g., 210 mcg weekly instead of 30 mcg daily.

[0052] In certain embodiments, the dose (D) in mcg is a daily dose or equivalent daily dose selected by the relationship D=(R×W) / F as a function of the patient's weight at the start of therapy in kilograms (W) and the desired increase in serum 25-hydroxyvitamin D in ng / ml (R), including a scaling factor (F), where F is in the range of about 50 to about 80, or about 55 to about 80, or about 60 to about 75, or about 68 to about 72, or about 69 to about 71, or about 70. For example, a 70 kg patient needing a 40 ng / ml increase in serum 25-hydroxyvitamin D can be given a daily dose of 40 mcg, and a 120 kg patient needing a 40 ng / ml increase in serum 25-hydroxyvitamin D can be given a daily dose of 70 mcg. In another type of embodiment, the scaling factor F can have an additional component based on the patient's weight at the start of therapy, e.g., a patient with a higher weight will receive a relatively higher mcg / kg dose compared to a patient with a relatively lower weight (e.g., F=f-(YxW)), where f is in the range of about 60 to about 80, or about 65 to about 75, or about 68 to about 72, or about 69 to about 71, or about 70, and Y is a unitless adjustment factor in the range of 0.01 to 0.1).

[0053] The foregoing dose selections can be used in any other manner that is an aspect of the disclosure herein, optionally in combination with other dosing and result factors described herein.

[0054] In any method or use according to the disclosure herein, the effective administration of 25-hydroxyvitamin D may include avoiding to disturb calcium metabolism, or phosphorus metabolism, or markers thereof, or any combination of the above. For example, the method may include not significantly increasing serum calcium, or not significantly increasing serum phosphorus, or not significantly increasing FGF23, with respect to baseline concentration before treatment. The method may include not significantly increasing serum calcium and not significantly increasing serum phosphorus, with respect to baseline concentration before treatment. The method may include not significantly increasing serum calcium, not significantly increasing serum phosphorus, and not significantly increasing FGF23, with respect to baseline concentration before treatment. The method may avoid causing hypercalcemia, or avoid causing hyperphosphatemia, or avoid causing hypercalciuria, or avoid raising FGF23, with respect to baseline concentration before treatment. For example, the method may include not causing hypercalcemia and hyperphosphatemia. The method can include not causing hypercalcemia, hyperphosphatemia, and elevation of FGF23 relative to baseline levels before treatment.The method can include not causing hypercalcemia, hyperphosphatemia, hypercalciuria, and elevation of FGF23 relative to baseline levels before treatment.

[0055] In any method or use according to the disclosure herein, effective administration of 25-hydroxyvitamin D can include providing a relatively low average daily increase in serum total 25-hydroxyvitamin D, e.g., an average daily increase of 4 ng / mL or less, or 3.5 ng / mL or less, or 3 ng / mL or less, or 2 ng / mL or less, during the increase in serum total 25-hydroxyvitamin D to a steady-state target level. Optionally, the average daily increase in serum total 25-hydroxyvitamin D during the increase in serum total 25-hydroxyvitamin D can be at least 0.2 ng / mL, or at least 0.3 ng / mL, or at least 0.5 ng / mL, or at least 1 ng / mL, or at least 2 ng / mL, or at least 2.5 ng / mL, e.g., from about 0.2 ng / mL to about 4 ng / mL, or from about 0.2 ng / mL to about 3.5 ng / mL, or from about 0.2 ng / mL to about 3ng / mL, or about 0.2ng / mL to about 2.5ng / mL, or about 0.2ng / mL to about 2ng / mL, or about 0.2ng / mL to about 1ng / mL, or about 0.3ng / mL to about 4ng / mL, or about 0.3ng / mL to about 3.5ng / mL, or about 0.3ng / mL to about 3ng / mL, or about 0.3ng / mL to about 2.5ng / mL, or about 0.3ng / mL to about 2ng / mL, or about 0.3ng / mL to about 1ng / mL. An upper limit of about 3ng / mL is specifically contemplated. Similarly, the maximum serum total 25-hydroxyvitamin D rise (ΔC 24) may be 4 ng / mL or less, or 3.5 ng / mL or less, or 3 ng / mL or less, or 2 ng / mL or less, and optionally at least 0.2 ng / mL, or at least 0.3 ng / mL, or at least 0.5 ng / mL, or at least 1 ng / mL, or at least 2 ng / mL, or at least 2.5 ng / mL, e.g., from about 0.2 ng / mL to about 4 ng / mL, or from about 0.2 ng / mL to about 3.5 ng / mL, or about 0.2 ng / mL The range may be from about 0.1 to about 3 ng / mL, or from about 0.2 ng / mL to about 2.5 ng / mL, or from about 0.2 ng / mL to about 2 ng / mL, or from about 0.2 ng / mL to about 1 ng / mL, or from about 0.3 ng / mL to about 4 ng / mL, or from about 0.3 ng / mL to about 3.5 ng / mL, or from about 0.3 ng / mL to about 3 ng / mL, or from about 0.3 ng / mL to about 2.5 ng / mL, or from about 0.3 ng / mL to about 2 ng / mL, or from about 0.3 ng / mL to about 1 ng / mL. An upper limit of about 3 ng / mL is particularly contemplated.

[0056] In an alternative method according to the disclosure herein, the method provides a method for providing a circulating blood plasma concentration of about 0.2 ng / mL to about 30 ng / mL, which may be greater than 3 ng / mL, e.g., at least 0.2 ng / mL, 0.3 ng / mL, 1 ng / mL, 2 ng / mL, 3 ng / mL, 5 ng / mL, or 10 ng / mL, and up to 30 ng / mL, or 20 ng / mL, or 10 ng / mL, optionally by less frequent administration, e.g., monthly, biweekly, or weekly. or 0.3ng / mL to 10ng / mL, or 0.3ng / mL to 20ng / mL, or >3ng / mL to 30ng / mL, or >3ng / mL to 20ng / mL, or >3ng / mL to 10ng / mL, or >3ng / mL to 7ng / mL, or >3ng / mL to <7ng / mL, or >3ng / mL to 6ng / mL, or >3ng / mL to 5ng / mL, or >3ng / mL to 4ng / mL; 24while providing a relatively low average daily increase in serum total 25-hydroxyvitamin D, for example, of 4 ng / mL or less, or 3 ng / mL or less, or 2 ng / mL or less, and optionally of at least 0.2 ng / ml, or at least 0.3 ng / ml, while increasing serum total 25-hydroxyvitamin D to a steady-state target level.

[0057] In another alternative method according to the disclosure herein, the method provides a method for administering a serotonin-releasing hormone (SHR) to a patient having a serotonin-releasing hormone (SHR) level of about ΔC, which may be in the range of at least 0.2 ng / ml, 0.3 ng / ml, 1 ng / ml, 2 ng / ml, 3 ng / ml, 5 ng / ml, or 10 ng / ml and up to 30 ng / ml, or 20 ng / ml, or 10 ng / ml, for example, from about 0.2 ng / ml to 30 ng / ml, or 0.3 ng / ml to 10 ng / ml, or 0.3 ng / ml to 20 ng / ml, or >3 ng / ml to 30 ng / ml, >3 ng / ml to 20 ng / ml, or >3 ng / ml to 10 ng / ml, or >3 ng / ml to 7 ng / ml, or >3 ng / ml to <7 ng / ml, or >3 ng / ml to 6 ng / ml, or >3 ng / ml to 5 ng / ml, or >3 ng / ml to 4 ng / ml, optionally with less frequent administration, for example monthly, biweekly, or weekly. 24 while providing an average daily increase in serum total 25-hydroxyvitamin D of about 0.2 ng / mL to about 10 ng / mL, or about 0.3 ng / mL to about 10 ng / mL, or about 0.5 ng / mL to about 10 ng / mL, or about 1 ng / mL to about 10 ng / mL, e.g., 3 ng / mL or less, or 2 ng / mL or less, and optionally at least 0.2 ng / ml, or at least 0.3 ng / ml, while increasing serum total 25-hydroxyvitamin D to a steady-state target level.

[0058] In any method or use according to the disclosure herein, effective administration of 25-hydroxyvitamin D can include increasing serum total 25-hydroxyvitamin D to a steady state level over a period of at least 8 weeks, or at least 10 weeks, or at least 12 weeks, or at least 14 weeks, e.g., 8-14 weeks, 8-12 weeks, or 10-12 weeks. For example, effective administration of 25-hydroxyvitamin D can increase serum total 25-hydroxyvitamin D to about 50 to about 300 ng / mL, or about 50 to about 200 ng / mL, or about 50 to about 100 ng / mL, or greater than 50 to about 300 ng / mL, or greater than 50 to about 100 ng / mL, over a period of at least 8 weeks, at least 10 weeks, or at least 12 weeks, or at least 14 weeks, e.g., 8-14 weeks, 8-12 weeks, or 10-12 weeks. 200 ng / mL, or in the range of greater than 50 to about 100 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, optionally about 60 to about 300 ng / mL, or about 60 to about 200 ng / mL, or about 60 to about 100 ng / mL, or greater than 60 to about 300 ng / mL, or greater than 60 to about 200 ng / mL, or greater than 60 to about 100 ng / mL or greater.

[0059] In any of the methods or uses disclosed herein, the effective administration of 25-hydroxyvitamin D may include administering 25-hydroxyvitamin D to increase the patient's serum total 1,25-dihydroxyvitamin D to a steady state level in the range of at least 40 pg / mL, or at least 45 pg / mL, and optionally up to 62 pg / mL, for example, 40 pg / mL or 45 pg / mL.

[0060] In any of the methods or uses disclosed herein, the patient may be a patient who is vitamin D deficient at the start of therapy, for example, has less than 30 ng / mL of serum total 25-hydroxyvitamin D. Optionally, the patient may have less than 30 ng / mL of serum total 25-hydroxyvitamin D at the start of therapy.

[0061] In any of the methods or uses disclosed herein, the patient may be a patient with greater than or about 30 ng / mL of serum total 25-hydroxyvitamin D at the start of therapy. Optionally, the patient may be a patient with greater than or about 40 ng / mL of serum total 25-hydroxyvitamin D at the start of therapy.

[0062] In any of the methods or uses disclosed herein, the patient may be a patient with CKD, optionally with CKD stages 3-5, or stages 3-4, or stage 5. Optionally, the patient may also be a patient being treated with hemodialysis.

[0063] The method can include 25-hydroxyvitamin D therapy to reduce plasma iPTH levels. The method can include 25-hydroxyvitamin D to reduce plasma iPTH by at least about 15%, e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, compared to pre-treatment levels. In another embodiment, repeated doses of 25-hydroxyvitamin D are optionally administered to a patient population in an amount effective to reduce the mean plasma intact PTH level of the patient population by at least about 15%, e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, compared to pre-treatment levels.

[0064] The method can include 25-hydroxyvitamin D therapy to increase bone mineral density, for example, until T-score is at least -2.5, or greater than -2.5, or at least -2.0, or at least -1.5, or at least -1.0, or greater than -1.0. The method can include 25-hydroxyvitamin D therapy to reduce blood levels of bone resorption markers, such as one or more of serum total alkaline phosphatase, BSAP, CTX-1, P1NP, and FGF-23. For example, the marker can be reduced to within the reference range of laboratory measurement techniques. In another embodiment, the marker can be reduced by at least about 10%, or at least about 20%, or at least about 30%.

[0065] In another embodiment, the method may include administering 25-hydroxyvitamin D therapy as described herein in the absence of 1,25-dihydroxyvitamin D therapy, or in the absence of calcitriol therapy, or in the absence of doxercalciferol therapy, or in the absence of alphacalcidol therapy, or in the absence of paricalcitol therapy, or in the absence of maxacalcitol therapy, or in the absence of falecalcitriol therapy, or in the absence of active vitamin D analog therapy.

[0066] In another embodiment, the methods can include administering 25-hydroxyvitamin D therapy as described herein and in the absence of cinacalcet therapy.

[0067] In another embodiment, the method can include administration of 25-hydroxyvitamin D therapy as described herein, and simultaneous administration of cinacalcet therapy.

[0068] 25-hydroxyvitamin D can be administered in any form, but in one embodiment, 25-hydroxyvitamin D can be administered by modified release, such as sustained release or delayed sustained release. For example, sustained release can be achieved by oral dosage forms, or sustained release can be achieved by transdermal patches. In another embodiment, sustained delivery can be provided by slowly injecting or infusing the compound over time, such as slowly pushing intravenous delivery. For example, intravenous delivery can be performed for at least 1 hour, optionally for 1 hour to 5 hours. Administration can be performed, for example, in parallel with hemodialysis treatment. In another embodiment, administration can be performed while the patient is not undergoing hemodialysis.

[0069] In certain embodiments, 25-hydroxyvitamin D is administered orally.For example, 25-hydroxyvitamin D can be administered in oral sustained release formulation.In an alternative method, 25-hydroxyvitamin D can be administered in multiple doses over an extended period of time throughout the day in oral immediate release formulation to produce a pharmacokinetic profile of serum 25-hydroxyvitamin D similar to that achieved by oral sustained release formulation.

[0070] In any of the methods or uses disclosed herein, the effective administration of 25-hydroxyvitamin D can include administering 25-hydroxyvitamin D to avoid substantial induction of CYP24A1. For example, the method can include administering 25-hydroxyvitamin D to achieve a vitamin D metabolite ratio (VMR), calculated as serum 24,25-dihydroxyvitamin D3 / serum total 25-hydroxyvitamin D3×100, of 5 or less, or 4.8 or less.

[0071] Hyperparathyroidism may be caused by chronically low serum calcium levels, vitamin D deficiency, and kidney disease. Hyperparathyroidism may also be caused by benign tumors (adenomas) or, less commonly, cancerous tumors of the parathyroid glands. Hyperparathyroidism may also be caused by enlargement of two or more parathyroid glands (hyperplasia). Hyperparathyroidism may be caused by other dysfunction of the parathyroid glands, such as parathyroid hypertrophy, multiple endocrine neoplasia, radiation exposure, and the use of lithium therapy. Parathyroid tumors that cause hyperparathyroidism include multiple endocrine neoplasia MEN1 and MEN2A.

[0072] Diseases and conditions associated with increases in plasma iPTH above normal baseline values ​​include renal osteodystrophy, osteitis fibrosa cysticum, osteomalacia, osteoporosis, osteopenia, extraskeletal calcification, and related disorders such as bone pain, periarthritis, and Mockerberg sclerosis. Soft tissue and vascular calcification, including pulmonary vascular calcification and pulmonary hypertension, cardiovascular disease, and uremic minimal arterial calcification (CUA), are additional serious consequences of hyperparathyroidism. Other symptoms of hyperparathyroidism include alterations in cardiovascular structure and function. Immune dysfunction, renal anemia, neuropathy, hematological abnormalities, and endocrine dysfunction. Hyperparathyroidism may be associated with the age-related vitamin D deficiency (ARVDD) syndrome.

[0073] Controlled release compositions intended for oral administration can be designed to contain 25-hydroxyvitamin D2 and / or 25-hydroxyvitamin D3 at a concentration of 1 to 1000 μg per unit dose and can be prepared, for example, to provide a substantially constant release of 25-hydroxyvitamin D2 and / or 25-hydroxyvitamin D3 over an extended period of time, for example at least 4 hours, or at least 8 hours, or at least 12 hours, or at least 24 hours.

[0074] Preparation of sustained release forms of 25-hydroxyvitamin D suitable for oral administration can be carried out according to many different techniques. For example, one or more 25-hydroxyvitamin D compounds can be dispersed in a matrix, i.e., a selected mixture of rate-controlling components and excipients in a selected ratio can be dispersed in a matrix and optionally covered with a coating material. Alternatively, one or more different coating techniques can be utilized to control the release rate of 25-hydroxyvitamin D from pharmaceutical formulations. For example, the coating can gradually dissolve over time, thereby exposing the dosage form contents, optionally contained in the matrix, to the body fluids of the local environment. In certain embodiments, after the coating becomes permeable, 25-hydroxyvitamin D diffuses through the coating, for example, from the outer surface of the matrix contained within the coating. When 25-hydroxyvitamin D is exhausted or depleted at the surface of such a matrix, the underlying reserves begin to be depleted by diffusion through the matrix to the external solution. In another type of embodiment, the release of 25-hydroxyvitamin D through the permeable coating or structure is affected by the gradual disintegration or erosion of the matrix contained therein, for example, the solubility of one or more components of the matrix. In another type of embodiment, the release of 25-hydroxyvitamin D is by the gradual disintegration or erosion of the matrix, for example, the solubility of one or more components of the matrix, and / or by the lack of physical integrity, the absence of any coating or other structure surrounding the matrix. The dosage form may optionally further comprise another active agent in the same region as 25-hydroxyvitamin D or in a different region. For example, the additional active agent may include calcium.

[0075] In one embodiment, the formulation provides one or more 25-hydroxyvitamin D compounds within a matrix that releasably binds components for sustained release when exposed to the contents of the gastrointestinal tract, e.g., the stomach, small intestine, or colon.

[0076] In one embodiment of the present invention, a controlled release oral formulation of 25-hydroxyvitamin D is generally prepared according to the following procedure: A sufficient amount of 25-hydroxyvitamin D, e.g., calcifediol, is completely dissolved in a minimum volume of USP grade absolute ethanol (or other suitable solvent) and mixed with suitable amounts and types of pharmaceutical grade excipients to form a matrix that is solid or semi-solid at room temperature and at normal human body temperature. The matrix slowly disintegrates in the intestine and / or colon.

[0077] In a preferred formulation, the matrix binds the 25-hydroxyvitamin D compound such that the 25-hydroxyvitamin D is released slowly and relatively steadily, e.g., substantially constantly, by simple diffusion and / or gradual breakdown into the contents of the small intestine and / or colon over a period of 4 to 8 hours or longer.

[0078] As noted above, the means for providing controlled release of 25-hydroxyvitamin D may be selected from any suitable controlled release delivery system, including any of the known controlled release delivery systems that deliver the active ingredient over a period of about 4 hours or more, including wax matrix systems, and the EUDRAGIT RS / RL system (Rohm Pharma, GmbH, Weiterstadt, Germany).

[0079] The wax matrix system provides a type of lipophilic matrix. The wax matrix system may utilize, for example, beeswax, white wax, sperm whale wax, or similar compositions. In certain embodiments, the wax is a non-digestible wax, for example, paraffin. The active ingredient is dispersed in a wax binder, which slowly disintegrates in intestinal fluids to gradually release the active ingredient. The wax binder impregnated with 25-hydroxyvitamin D may be filled into a softgel capsule. The softgel capsule may include one or more gel-forming agents, for example, gelatin, starch, carrageenan, and / or other pharma-ceutically acceptable polymers. In one embodiment, a partially cross-linked soft gelatin capsule is used. Alternatively, a vegetable-based capsule may be used. In the wax matrix system, the active ingredient is dispersed in a wax binder, which softens at body temperature and slowly disintegrates in intestinal fluids to gradually release the active ingredient. The system can suitably include a mixture of waxes, with optional additional oils, to achieve a melting point above body temperature but below the melting temperature of the selected formulation used to make the soft or hard capsule shell, or vegetable capsule shell, or other formulation used to make the shell casing or other coating.

[0080] Specifically, in a preferred embodiment, the wax selected for the matrix is ​​melted and thoroughly mixed. The desired amount of oil is then added, followed by thorough mixing and homogenization. The waxy mixture is then gradually cooled to a temperature just above its melting point. The desired amount of 25-hydroxyvitamin D dissolved in ethanol is uniformly distributed into the molten matrix, and the matrix is ​​filled into a capsule, for example, a vegetable-based or gelatin-based capsule. The filled capsule is optionally treated with a solution containing an aldehyde, such as acetaldehyde, for an appropriate time to partially crosslink the polymer, for example, gelatin, in the capsule shell when in use. The capsule shell is gradually crosslinked over a period of weeks, thereby becoming more resistant to dissolution in the contents of the stomach and upper intestine. If properly constructed, this gelatin shell will gradually dissolve after oral administration, and by the time it reaches the small intestine, it will be sufficiently porous (without completely disintegrating) to allow 25-hydroxyvitamin D to slowly diffuse out of the wax matrix into the contents of the small intestine and / or colon.

[0081] Examples of other lipid matrices suitable for use in the methods of the present invention include one or more of glycerides, fatty acids and fatty alcohols, and fatty acid esters.

[0082] The wax matrix may contain a stabilizing component that stabilizes the release characteristics of the dosage form over its expected shelf life. The stabilizing component may be a cellulose component, such as a cellulose ether, e.g., hydroxylpropylmethylcellulose.

[0083] In one embodiment, the formulation may include an oil vehicle for the 25-hydroxyvitamin D compound. Any pharma- ceutically acceptable oil may be used. Examples include animal (e.g., fish), vegetable (e.g., soybean), and mineral oils. The oil is preferably one that easily dissolves the 25-hydroxyvitamin D compound used. The oil vehicle may include mineral oil, particularly non-digestible oils such as liquid paraffin, and squalene. The ratio of wax matrix to oil vehicle may be optimized to achieve the desired release rate of the 25-hydroxyvitamin D compound. Thus, when a heavier oil component is used, relatively less wax matrix may be used, and when a lighter oil component is used, relatively more wax matrix may be used.

[0084] Another suitable controlled release oral drug delivery system is the EUDRAGIT RL / RS system in which the active 25-hydroxyvitamin D ingredient is formed into granules, for example, 25 / 30 mesh in size. The granules are then uniformly coated with a thin polymer lacquer, which is water insoluble but slowly water permeable. The coated granules can be mixed with optional additives, including one or more of antioxidants, stabilizers, binders, lubricants, processing aids, and the like. The mixture can be compressed into a hard, dry tablet that can be further coated prior to use, or can be poured into a capsule. When the tablet or capsule is swallowed and comes into contact with gastric and intestinal fluids, the thin lacquer begins to swell, slowly allowing the intestinal fluids to penetrate. As the intestinal fluids slowly penetrate the lacquer coating, the contained 25-hydroxyvitamin D is slowly released. By the time the tablet or capsule passes through the small intestine, about 4-8 hours or later, the 25-hydroxyvitamin D has been slowly, but completely, released. Thus, when ingested, the tablet continuously releases 25-hydroxyvitamin D, as well as any other active ingredients.

[0085] The EUDRAGIT system consists of a high-permeability lacquer (RL) and a low-permeability lacquer (RS). RS is a water-insoluble film-forming agent based on a neutral swellable methacrylate ester and a small amount of trimethylammonioethyl methacrylate chloride, with a molar ratio of quaternary ammonium groups to neutral ester groups of approximately 1:40. RL is also a water-insoluble swellable film-forming agent based on a neutral methacrylate ester and a small amount of trimethylammonioethyl methacrylate chloride, with a molar ratio of quaternary ammonium groups to neutral ester groups of approximately 1:20. The permeability of the coating, and therefore the time course of drug release, can be adjusted by changing the ratio of RS to RL in the coating material. For details of the Eudragit RL / RS system, see the technical publications available from Rohm Tech, Inc. 195 Canal Street, Maiden, Mass., 02146 and K. Lehmann, D. Dreher “Coating of tablets and small particles with acrylic resins by fluid bed technology,” Int. J. Pharm. Tech. & Prod. Mfr. 2(r), 31-43 (1981), which are incorporated herein by reference.

[0086] Other examples of insoluble polymers include polyvinyl esters, polyvinyl acetals, polyacrylic esters, butadiene styrene copolymers, and the like.

[0087] The dosage form may also contain adjuvants such as preservatives or stabilizing adjuvants.For example, a preferred formulation comprises 25-hydroxyvitamin D (e.g., about 30 μg, about 60 μg, or about 90 μg of 25-hydroxyvitamin D3), about 2% by weight absolute ethanol, about 10% by weight lauroyl polyoxyl glyceride, about 20% by weight solid paraffin, about 23% by weight glycerol monostearate, about 35% by weight liquid paraffin or mineral oil, about 10% by weight hydroxypropyl methylcellulose, and optionally a small amount of antioxidant preservative (e.g., butylated hydroxytoluene).The formulation according to the present invention may also contain other substances of therapeutic value, or may contain a mixture of two or more compounds specified in this specification and claims.

[0088] As an alternative to oral 25-hydroxyvitamin D, intravenous administration of 25-hydroxyvitamin D is also contemplated. In one embodiment, 25-hydroxyvitamin D is administered as a sterile intravenous bolus, optionally as a bolus injection of a composition that provides a sustained release profile. In another embodiment, 25-hydroxyvitamin D is administered via gradual injection / infusion, for example, over 1-5 hours, to provide a controlled or substantially constant release of 25-hydroxyvitamin D to DBP in the patient's blood. For example, the composition may be injected or infused over at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours. In one embodiment, a composition intended for intravenous administration according to the present invention is designed to contain a concentration of 1-100 μg of 25-hydroxyvitamin D compound per unit dose. Sterile isotonic formulations of 25-hydroxyvitamin D can be prepared by dissolving 25-hydroxyvitamin D in absolute ethanol, propylene glycol or another suitable solvent and combining the resulting solution with one or more surfactants, salts, and preservatives in an appropriate amount of water for injection. Such formulations can be administered slowly from a syringe, for example, via a heparin lock or by addition to a larger volume of sterile solution (e.g., saline) that is steadily infused over time.

[0089] Suitable sustained release dosage forms of 25-hydroxyvitamin D are described, such as in the following U.S. patents and published U.S. patent applications, the disclosures of which are incorporated by reference herein: 2010 / 0120728A1, 2010 / 0144684A1, 2013 / 0137663A1, 8,329,677, 8,361,488, 8,426,391, 8,962,239, and 9,861,644.

[0090] The following examples are provided merely to illustrate the present invention and not to limit its scope in any way. EXAMPLES

[0091] The following examples are offered for illustrative purposes and are not intended to limit the scope of the invention.

[0092] Example 1 Adult subjects (n=429) with SHPT, VDI, and stage 3 or 4 CKD were stratified by stage and treated daily with either extended-release calcifediol (ERC) or placebo in two identical parallel randomized double-blind studies. After 26 weeks of treatment, all subjects were ranked by serum total 25-hydroxyvitamin D levels and divided into quintiles to examine the relationship between the degree of vitamin D supplementation and associated changes in plasma iPTH, serum bone turnover markers, calcium, phosphorus, intact fibroblast growth factor 23 (FGF23) and vitamin D metabolites, estimated glomerular filtration rate (eGFR), and urinary calcium-to-creatinine (Ca:Cr) ratio.

[0093] Specifically, two identical 26-week multicenter trials using a randomized, double-blind, placebo-controlled design enrolled a total of 429 subjects from 89 US sites with SHPT (plasma iPTH ≥ 85 and < 500 pg / mL), stage 3 or 4 CKD (eGFR ≥ 15 and < 60 mL / min / 173 m2), and VDI (serum total 25-hydroxyvitamin D ≥ 10 and < 30 ng / mL). Other eligibility criteria included serum calcium ≥ 8.4 and < 9.8 mg / dL and serum phosphorus ≥ 2.0 and < 5.0 mg / dL. Exclusion criteria included spot urinary calcium:creatinine (Ca:Cr) ratio > 0.2, nephrotic range proteinuria (> 3 mg / mgCr), and a history of parathyroidectomy for SHPT or kidney transplantation. Subjects were enrolled in a phased manner at many different latitudinal sites to minimize seasonal variation in mean baseline serum total 25-hydroxyvitamin D. Details regarding these studies have been previously published by Sprague et al., Use of extended-release calcifediol to treat secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease, Am J Nephrol 2016;44:316-325, and Sprague et al., Extended-release calcifediol for secondary hyperparathyroidism in stage 3-4 chronic kidney disease, Expert Review of Endocrinology & Metabolism 2017;12:289-301, the disclosures of which are incorporated herein by reference.

[0094] Subjects were stratified by CKD stage and randomized in a 2:1 ratio to receive 30 μg of ERC (or matching placebo) orally once daily at bedtime for 12 weeks, followed by an additional 14 weeks of treatment with 30 or 60 μg of ERC (or placebo) once daily at bedtime. The daily dose was increased to 60 μg at the beginning of week 13 if plasma iPTH was >70 pg / mL (upper limit of laboratory reference range), serum total 25-hydroxyvitamin D was <65 ng / mL (to reduce the risk of driving values ​​>100 ng / mL), and serum calcium was <9.8 mg / dL. The sole primary efficacy endpoint was the proportion of subjects in the intention-to-treat (ITT) population who achieved a ≥30% mean reduction in plasma iPTH from pretreatment baseline during the efficacy evaluation period (EAP), defined as weeks 20 through 26 of treatment.

[0095] A total of 213 subjects participated in the first of these two RCTs (141 ERC and 72 placebo), 216 subjects participated in the other RCT (144 ERC and 72 placebo), and 354 subjects (83%) completed the study. Data from both RCTs were pooled because: (a) the studies were controlled by a common protocol, (b) they were conducted simultaneously using multiple sites within the continental United States, (c) the subject populations were similar according to inclusion criteria and actual baseline demographic and biochemical characteristics, and (d) the changes observed in serum total 25-hydroxyvitamin D, serum total 1,25-dihydroxyvitamin D, and plasma iPTH were similar during ERC or placebo treatment. Overall, 222 subjects (51.7%) had stage 3 CKD (151 ERC and 71 placebo) and 207 subjects (48.3%) had stage 4 CKD (134 ERC and 73 placebo).

[0096] The ITT population included all subjects (n=429) randomized to study medication. The mean age of subjects in the ITT population was 66 years (range 25-85 years), 50% were male, 65% were white, 32% were African American or black, 21% were Hispanic, and 3% were other. The most common causes of CKD were diabetes and hypertension, and the mean eGFR was 31 mL / min / 1.73 m. 2 It was.

[0097] The per-protocol (PP) population included all subjects (n=356) included in the EAP, defined as those without major protocol deviations and with at least two serum total 25-hydroxyvitamin D and two plasma iPTH measurements, calculated at baseline and from weeks 20 to 26 of treatment. Demographic and baseline data for the PP population are summarized in Table 1, grouped by CKD stage. Here, we report only the analysis of the PP population, as results were obtained that were not substantially different from those based on the analysis of the ITT population, and the number of subjects remained constant throughout the 26-week treatment period. Sixty-two ITT subjects were excluded because they discontinued treatment before the EAP, and 11 were excluded because of major protocol violations: receipt of prohibited concomitant medications (n=4), not meeting all inclusion criteria (n=3), medication compliance <80% (n=3), and premature unblinding (n=1). JPEG2025031720000001.jpg248164

[0098] Blood and spot urine samples were collected at weekly or biweekly intervals and analyzed during the applicable stability window (as stated in the validation report) at the OOD Global Central Laboratory (Highland Heights, KY). Plasma iPTH levels were determined by two-site sandwich electrochemiluminescence (Roche Elecsys, reference range 15-65 pg / mL, CV% 2.7). Serum total 25-hydroxyvitamin D was determined by chemiluminescence (DiaSorin) and serum total 1,25-dihydroxyvitamin D was determined by radioimmunoassay (IDS). Serum 25-hydroxyvitamin D3 (limit of quantification: 5.00 ng / mL, CV% 0.82-1.84 within-run and 2.01-4.26% between-run) and 24,25-dihydroxyvitamin D3 (limit of quantification: 0.52 ng / mL, CV% 2.18-4.60 within-run and 3.79-9.29 between-run) were determined by LC-MS (Syneos) for the purpose of calculating the vitamin D metabolite ratio (VMR), calculated as serum 24,25-dihydroxyvitamin D3 / serum total 25-hydroxyvitamin D3*100. Serum (but not plasma) intact FGF23 levels were determined by enzyme-linked immunosorbent assay (Millipore, reference range 0-50 pg / mL, CV% 10.6) due to its good recovery and long-term stability during validation. Serum collagen type 1 C-telopeptide (CTx-1) was measured by electrochemiluminescence (Roche Cobas, reference range 0-856 pg / mL, CV% 1.4). Intact procollagen type 1 N-terminal propeptide (P1NP) was determined by chemiluminescence immunoassay (Roche Cobas reference range 13.8-88 ng / mL, CV% 5.0), an assay that measures monomers that may accumulate in CKD patients and gives falsely elevated results. Bone-specific alkaline phosphatase (BSAP) was determined by ELISA (Quidel, reference range 14.9-42.4 U / L, CV% 7.7), an assay that measures activity rather than mass. Total alkaline phosphatase was measured by enzymatic assay (Roche Cobas, reference range 43-115 U / L, CV% 2.0). Other parameters were determined by standard procedures.Serum calcium levels were corrected for low albumin.

[0099] Changes from pretreatment baseline in mean serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and plasma iPTH in response to treatment with ERC or placebo were examined by CKD stage both mid-study (weeks 8–12 of treatment) and at EAP (weeks 20–26 of treatment). ERC increased mean serum 25-hydroxyvitamin D similar to placebo at both mid-study and EAP CKD stages (P<0.0001) (Figure 1A). ERC also increased mean serum 1,25-dihydroxyvitamin D and decreased mean plasma iPTH compared with placebo at both mid-study and EAP CKD stages (P<0.05–0.0001) (Figure 1B and 1C). Serum 1,25-dihydroxyvitamin D and plasma iPTH values ​​were expressed as percentages of baseline because mean baseline values ​​for subjects with stage 3 CKD differed from subjects with stage 4 CKD (Table 1). Due to the lack of stage-specific responses for these three major parameters, all subsequent analyses were performed without considering CKD stage.

[0100] Demographic and baseline data for P subjects grouped by post-treatment 25-hydroxyvitamin D quintiles are shown in Table 2. Analyses of plasma iPTH and serum bone turnover markers by treatment period and post-treatment 2-hydroxyvitamin D quintiles are shown in Table 3.

[0101] All subjects, regardless of whether they received ERC or placebo, were then ranked by their post-treatment (EAP) mean serum total 25-hydroxyvitamin D levels and divided into quintiles, with quintile 1 defined as subjects with the lowest levels and quintiles 2–5 as subjects with progressively higher levels. The mean (SE) post-treatment 25-hydroxyvitamin D values ​​for each quintile are listed at the top of Table 2, which summarizes the demographic and baseline characteristics of the PP subjects (by quintile), and on the left side of Table 3. The means for each quintile 2–5 were all significantly greater than the corresponding means for quintile 1 (p<0.0001). The proportions of subjects receiving placebo in quintiles 1 and 2 were 96% and 76%, respectively. There were no placebo-treated subjects in quintiles 3–5. Data for quintiles 2–5 were compared to data for quintile 1 by one-way analysis of variance followed by Bonferroni correction. Mean (SE) serum total 25-hydroxyvitamin D at baseline ranged from 16.1 (0.6) to 21.7 (0.6) ng / mL (P < 0.05) within individual quintiles. As described, significant variations between quintiles at baseline were also evident in mean weight, body mass index (BMI), and age, but no differences were detected in mean eGFR, or mean serum and urinary parameters related to mineral and bone metabolism.

[0102] Mean (SE) posttreatment serum total 1,25-dihydroxyvitamin D increased progressively across quintiles, from 34.3 (1.3) pg / mL in quintile 1 to 48.5 (2.1) pg / mL in quintile 5. The means of quintiles 2-5 were all significantly greater than the mean of quintile 1 (p<0.01).

[0103] Mean (SE) posttreatment serum 24,25-dihydroxyvitamin D3 gradually increased from 0.7 (0.04) in quintile 1 to 5.6 (0.27) ng / mL in quintile 5. Values ​​differed from quintile 1 only for the top two quintiles (P<0.05).

[0104] The mean (SE) posttreatment VMR gradually increased from 3.6 (0.22) in quintile 1 to 4.8 (0.22) in quintile 4 but then remained stable at 4.7 (0.19) in quintile 5.

[0105] Mean (SE) plasma iPTH trended upward during treatment in quintiles 1 and 2, which included mainly placebo subjects, but declined gradually in the top three quintiles (P<0.05) (Table 3 and Figure 2A). Mean iPTH after treatment was 166(10) pg / mL in quintile 1 and was significantly lower (P<0.001) in quintiles 3-5, reaching 115(6), 101(5), and 97(5) pg / mL, respectively (Figure 2B). The observed decline in iPTH appeared to attenuate as mean serum total 25-hydroxyvitamin D approached its highest levels. The proportion of subjects with a mean ≥30% decrease in plasma iPTH from pre-EAP treatment baseline was 8.5% in quintiles 1 and 2, then increased linearly to 27.8% in quintile 3, 42.3% in quintile 4, and 57.7% in quintile 5 (Figure 3).

[0106] Changes in mean (SE) serum CTx-1, P1NP, BSAP, and total alkaline phosphatase within a given quintile during the treatment period and across quintiles at the end of treatment were similar to those observed in plasma iPTH (Figures 2A and 2B).

[0107] Post-treatment means were within the normal range for all quintiles, except for P1NP, which remained elevated in quintiles 1–3.

[0108] Mean (SE) posttreatment levels of serum calcium and phosphorus were 9.3 (0.05) and 3.8 (0.06) mg / dL, respectively, in quintile 1 and showed a slight upward trend in the other four quintiles, reaching 9.45 (0.03) and 4.0 (0.07) mg / dL, respectively, in quintile 5. Mean (SE) posttreatment values ​​of eGFR and urinary Ca:Cr ratio ranged from 27.8 (1.1) to 32.3 (1.6) mL / min / 1.73 m , respectively, among the five quintiles. 2, and varied from 0.03 (0.004) to 0.04 (0.006) without any apparent trend. Mean (SE) posttreatment levels of serum intact FGF23 for quintiles 1 to 5 were 51.7 (9.6), 63.3 (16.1), 50.6 (8.7), 44.9 (7.5), and 62.8 (7.9) pg / mL, respectively. No significant differences were observed between quintile 1 and any of the upper quintiles (P = NS) for these five parameters.

[0109] SHPT progression, defined as a >10% increase in EOT iPTH from pretreatment baseline, was also calculated for each quintile.

[0110] Mean (SE) plasma iPTH levels at baseline and EOT, along with the proportion of subjects experiencing SHPT progression, are summarized below in Table 4 by quintiles of post-treatment serum total 25-hydroxyvitamin D. JPEG2025031720000002.jpg66169

[0111] More than one-third of subjects (quintiles 1 and 2) receiving inadequate vitamin D supplementation experienced SHPT progression. Mean iPTH and the proportion of subjects with SHPT progression were reduced only when ERC treatment increased mean serum total 25D to at least 51 ng / mL. Results indicate that serum total 25-hydroxyvitamin D targets above 50 ng / mL are required for attenuation of SHPT progression in stages 3-4 CKD.

[0112] This post-hoc analysis of pooled data from two identical 26-week prospective, multicenter, randomized, double-blind, placebo-controlled trials with ERC in patients with stage 3 or 4 CKD showed that mean reductions in plasma iPTH and serum bone turnover markers were proportional to increases in mean serum total 25-hydroxyvitamin D and independent of CKD stage. These findings support the conclusion that ERC suppresses elevated iPTH and bone turnover markers by gradually increasing circulating levels of 25-hydroxyvitamin D. Furthermore, a mean serum 25-hydroxyvitamin D level of at least 50.8 ng / mL was required to reduce iPTH, attenuate SHPT progression, and reduce bone turnover markers in CKD patients, far exceeding the clinical practice guideline goals of 20 or 30 ng / mL, suggesting that even higher levels than those assessed here may be required for iPTH normalization, if necessary. Higher levels of serum 25-hydroxyvitamin D are readily achieved with ERC treatment and are proportional to the dose administered. However, given the apparent attenuation of mean iPTH reduction at the highest level of mean serum total 25-hydroxyvitamin D examined herein (92.5 ng / mL), normalization of iPTH may not be achievable. This attenuation may be overcome with longer treatment or may provide both protection from oversuppression of iPTH and an indication of an appropriate target for iPTH reduction in patients with stage 3-4 CKD.

[0113] The current study showed that ERC gradually increased mean serum total 25-hydroxyvitamin D to 92.5 ng / mL over 26 weeks without adverse effects on mean serum calcium, phosphorus, FGF23, eGFR, VMR, or urinary Ca:Cr ratio, and did not increase mean serum 1,25-dihydroxyvitamin D above the ULN (62 pg / mL). Extending these studies to 52 weeks of ERC treatment did not show increased risks associated with these parameters. One observational study suggested a J-shaped association between serum 25-hydroxyvitamin D levels and all-cause mortality, while another study showed an increased hazard ratio only when serum 25-hydrovitamin D levels were low. The current study found a positive correlation between serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, but no correlation between serum total 25-hydroxyvitamin D and serum calcium or phosphorus. The manifestation of some symptoms of hypercalcemia observed in 2% of subjects treated with ERC appeared to be independent of serum total 25-hydroxyvitamin D. The data from this study also demonstrated that increasing 25-hydroxyvitamin D exposure not only attenuated the progressive rise in serum bone turnover markers but actually reduced the levels of these markers, suggesting improved management of high-turnover bone disease and reduced risk of associated adverse sequelae. Bone deterioration and resulting fractures are important causes of morbidity and mortality in CKD patients with SHPT. Even modestly elevated PTH has recently been demonstrated to cause profound changes in bone structure and reduce spinal BMD. Poor bone health is strongly associated with vascular calcification in CKD and associated high rates of cardiovascular morbidity and mortality, and there is great interest in diagnosing and correcting bone disease in patients with kidney disease to improve bone health and reduce health care costs.

[0114] Surprisingly, ERC treatment showed similar effects on serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and plasma iPTH in patients with stage 3 or 4 CKD. This finding challenges the conventional wisdom that as CKD progresses, calcifediol becomes less convertible to 1,25-dihydroxyvitamin D3 due to reduced expression of CYP27B1 in the remaining kidney. However, calcifediol can be activated extrarenally by CYP27B1 in the parathyroid gland and many other tissues. Extrarenal hormone production depends on sufficient circulating levels of 25-hydroxyvitamin D and may be possible at levels well above 20–30 ng / mL. The current findings indicate that (a) there is sufficient renal CYP27B1 activity in predialysis patients to activate 25-hydroxyvitamin D, and / or (b) 25-hydroxyvitamin D is activated by CYP27B1 expressed outside the kidney and released into the circulation. Although serum 24,25-dihydroxyvitamin D3 levels increased with ERC treatment, the VMR was only moderately elevated, suggesting that there was no substantial induction of CYP24A1.

[0115] Figures 5-8 show the relationship between patient weight and dose response in serum 25-hydroxyvitamin D levels after 12 weeks of treatment with ERC at 30 mcg per day. Figures 5-6 show the relationship between patient weight at the start of treatment (baseline) and serum 25-hydroxyvitamin D concentrations (both baseline-subtracted serum concentrations and actual serum concentrations) obtained after 12 weeks of treatment with ERC at 30 mcg per day. Figures 7-8 show the relationship between serum 25-hydroxyvitamin D and dose per baseline body weight (both baseline-subtracted serum concentrations and actual serum concentrations, respectively) after 12 weeks of treatment with ERC at 30 mcg per day.

[0116] In conclusion, pooled data from two large prospective RCTs showed that ERC safely increased 25-hydroxyvitamin D exposure in patients with stage 3 or 4 CKD to levels well above those recommended by current clinical practice guidelines. Mean serum total 25-hydroxyvitamin D levels of at least 50.8 ng / mL were associated with proportional increases in serum 1,25-hydroxyvitamin D, decreases in plasma iPTH and serum bone turnover markers, and attenuated SHPT progression defined as a >10% increase in EOT iPTH from pretreatment baseline, without adverse changes in mean serum calcium, phosphorus, FGF23, eGFR, or urinary Ca:Cr ratio. Elevation of mean serum total 25-hydroxyvitamin D to 92.5 ng / mL was insufficient to normalize plasma iPTH, suggesting that higher exposures may be necessary to optimally treat SHPT in stage 3 or 4 CKD.

[0117] Example 2 This example describes a structured chart review of patients with stage 3 or 4 chronic kidney disease who had vitamin D deficiency and secondary hyperparathyroidism and were being treated with extended-release calcifediol or other relevant comparators. This study is related to Predialysis Mineral and Bone Disorders: A Real-World Assessment of the Risk and Effectiveness of Current SHPT Treatment Approaches (MBD-AWARE).

[0118] the purpose The overall objective of this study was to generate preliminary real-world evidence demonstrating: (a) the safety and efficacy of extended-release calcifediol (ERC) for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI); and (b) the utilization, safety, and efficacy of other vitamin D therapies (OVDTs) considered standard of care for SHPT in the treatment of these patients. OVDTs consist of nutritional vitamin D (NVD), defined as orally administered ergocalciferol or cholecalciferol, or active (1α-hydroxylated) vitamin D analogs (VDAs), defined as orally administered calcitriol, paricalcitol, or doxercalciferol.

[0119] The specific objectives of the study were to describe or estimate the following in each of the three cohorts (defined in the study design below) before and during the 6-month follow-up period: (1) changes in serum calcium and phosphorus, (2) changes in serum total 25-hydroxyvitamin D (25D) and parathyroid hormone (PTH) levels, (3) achievement of normal 25D levels, (4) achievement of ≥30% PTH reduction, and (5) changes in ancillary laboratory values.

[0120] Background technology ERC 30mcg capsules were approved by the Food and Drug Administration in June 2016 for the treatment of SHPT in adult patients with stage 3 or 4 CKD and VDI. The active ingredient, calcifediol, is 25-hydroxyvitamin D3 and is the physiological precursor of 1,25-dihydroxyvitamin D3 (calcitriol), the vitamin D hormone of VDI. Calcifediol is synthesized in the liver from vitamin D3 (cholecalciferol). Vitamin D3 is produced endogenously in the skin after exposure to sunlight or obtained from diet or supplements. Another prohormone, 25-hydroxyvitamin D2, is synthesized in the liver from vitamin D2 (ergocalciferol), which cannot be produced endogenously and can only be obtained from diet or supplements. These two prohormones are collectively referred to as "25-hydroxyvitamin D." Essentially all of the 25-hydroxyvitamin D in the blood consists of calcifediol unless an individual is receiving significant amounts of ergocalciferol supplementation.

[0121] CKD is a steadily growing health problem in the United States (US), driven by an aging population and the increasing prevalence of obesity with complications related to hypertension and diabetes. CKD is classified into five stages, each defined by an estimated glomerular filtration rate (eGFR) range that gradually decreases from stage 1 to stage 5. Abnormalities in mineral metabolism and bone histology begin in the early stages of CKD and worsen as eGFR declines [Levin et al 2007]. Even minimal declines in eGFR are associated with increased risk of bone loss (osteoporosis) and incidence of hip fractures. Comorbidities associated with CKD include SHPT, VDI, extensive soft tissue calcification, cardiovascular (CV) disease, infections, and reduced quality of life [Souberbielle et al 2010].

[0122] Vitamin D insufficiency (VDI) in CKD patients is caused by nutritional deficiencies, reduced exposure to sunlight, proteinuria, decreased hepatic synthesis of calcifediol, and overexpression of the vitamin D catabolic enzyme CYP24A1 [Helvig et al. 2010]. It is widely accepted that serum total 25D is the best indicator of a patient's vitamin D status. Serum total 25-hydroxyvitamin D (25D) levels of ≥ 30 ng / mL are considered adequate in CKD patients, while levels < 30 ng / mL are considered "insufficient" [Holick et al. 2011]. The commonly used reference range for serum total 25D is 30-100 ng / mL [Souberbielle et al. 2010]. Observational studies have shown that in CKD patients, higher 25D levels may be required to achieve PTH targets due to a decline in glomerular filtration rate (GFR) [Ennis et al. 2016].

[0123] Serum total 25D levels in the general population vary with many factors, including sunlight intensity (which varies by geographic location and season), sun exposure (which is influenced by skin pigmentation, sunscreen use, and other cultural factors), age, and dietary intake [Holick 1995]. Levels tend to be lower at higher latitudes during the winter. In patients with CKD, low total serum 25D levels (VDI) are independent of season or latitude and become more common as kidney disease progresses.

[0124] Because renal and extrarenal production of calcitriol depends on an adequate supply of calcifediol, VDI leads to insufficient calcitriol production. Decreased renal function further impairs the conversion of calcifediol to calcitriol by renal 1α-hydroxylase (CYP27B1). Chronically low circulating calcitriol reduces intestinal absorption of dietary calcium and increases secretion of PTH by the parathyroid gland, ultimately resulting in SHPT.

[0125] Clinical practice guidelines for the treatment of SHPT in CKD recommend regular screening for elevated PTH beginning in patients with stage 3 CKD. Guidelines issued by the National Kidney Foundation from the Kidney Disease Outcomes Quality Initiative (KDOQI) [National Kidney Foundation.KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease 2003, Guideline 8A], the more recent Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) [Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group 2009], and the latest updated KDIGO guidelines [KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD recommends testing for VDI if elevated PTH is encountered and correcting it with aggressive vitamin D supplementation. However, the medical literature describes how in patients with stage 3 or 4 CKD, serum total D is inconsistently or inadequately treated with NVD (ergocalciferol or cholecalciferol) supplementation and elevated PTH remains uncorrected by the NVD.Since 1973, over 30 trials have been published in which ergocalciferol or cholecalciferol was administered to patients with stages 3–5 CKD. The overall conclusion from this body of work has been summarized by Kalantar-Zadeh and Kovesdy: “Most of these trials have shown no, minimal or insufficient changes in PTH levels, or changes that still do not meet the K / DOQI recommended target range for PTH, usually only in some stages of CKD” [Kalantar-Zadeh and Kovesdy 2009]. A recent review of published randomized clinical trials concluded that vitamin D is ineffective in lowering iPTH levels in patients with stages 3–5 CKD [Agarwal and Georgianos 2016]. Thus, there is a need for effective treatments to increase serum total 25D and control elevated iPTH in this patient population. The ERC aims to meet this urgent need.

[0126] Rationale Evidence of safety and efficacy of ERC as treatment for SHPT in adult patients with stage 3 or 4 CKD and VDI has been demonstrated in randomized controlled clinical trials [Sprague et al. 2016, Sprague et al. 2017]. However, given the recency of marketing authorization, data originating from real-world settings regarding the utilization, safety, and efficacy of ERC in these patients is lacking. Additionally, there is limited evidence regarding the current utilization, safety, and efficacy of OVDTs, which are considered standard of care. This retrospective study aimed to generate new real-world evidence regarding the utilization, safety, and efficacy of ERCs and OVDTs in the United States.

[0127] Study design and methodology Eighteen US nephrology clinics participated in the study and provided medical records of the first 376 patients who met study inclusion criteria for retrospective analysis. A screening tool was developed to serve as a data entry portal for participating clinics. Data were collected until a cut-off date determined by study investigators.

[0128] Study population A total of 376 patients were recruited and enrolled in this retrospective study. Patients were considered to meet the study inclusion criteria if they had a history of stage 3 or stage 4 CKD, VDI and SHPT, and were documented to have started treatment with ERC, NVD or VDA on or after the date. It was found that 1,917 subjects were screened for eligibility. However, the actual number is unknown as the sites may have screened subjects before attempting or entering eligible patients in the data collection tool. Patients who met the inclusion criteria were grouped into three cohorts: 1) the ERC Any Use (ERCAU) cohort, defined as patients who used ERC for at least 1 month; 2) the nutritional vitamin D (NVD) cohort, defined as patients who used nutritional vitamin D (ergocalciferol or cholecalciferol) for at least 1 month; and (nutritional vitamin D was presented converted to total weekly dose); and 3) the activated vitamin D analogue (VDA) cohort, defined as patients who used active (1α-hydroxylated) vitamin D analogues (calcitriol, paricalcitol, or doxercalciferol) for at least 1 month.

[0129] Figure 4 shows the distribution of patients among the study cohorts.

[0130] Selection Criteria All patients included in the study had SHPT (PTH above the upper limit of normal (ULN) for the test), VDI (serum total 25D < 30 ng / mL), and stage 3 or 4 CKD (eGFR ≥ 15 to < 60 mL / min / 1.73 m on the index date (defined below)). 2) and fulfilled the criteria for inclusion in one of the three cohorts above (see Study Population).

[0131] All included patients were assigned an index date, defined as the date of first treatment with ERC or OVDT. When defining the index date, the following criteria had to be met for each patient to be considered eligible for the study: Available medical records ≥ 6 months prior to the index date (baseline records), Available medical records ≥ 6 months after the index date (follow-up records), receive only one SHPT therapy of interest during the follow-up period, with the exception of changes in active (1α-hydroxylated) VDA, and do not switch therapy during this period; Patients who were Rayaldee and VDA naïve in the 3 months prior to the index date, At least one available serum total 25D and PTH measurement within 1 year prior to the index date, and At least one available 25D and PTH measurement 6 months after the index date and within 30 days of treatment cessation.

[0132] Source Data Source data for this study included: Electronic or paper medical records: Data on diagnosis, past medical history, treatments, and other resource utilization were captured for 6 months prior to the index date and for at least 6 months after the index date. Data type, level, and collection date were collected. It is possible that patients sought care outside the selected facilities. Some medical records may have been incomplete (as resource utilization from other facilities could not always be captured), especially as outpatient visits related to comorbid conditions related to CKD, such as CV disease. Data points that may have introduced potential information bias were captured and flagged across all participating facilities. Other data points available for some, but not all, participating facilities, and for some, but not all patients within the clinic, were also flagged and analyzed in subgroup analyses. To supplement patient data, other medical records from other care settings were incorporated when available, such as emergency room visits, outpatient visits, and pharmacy information. Laboratory Laboratory Database: Any laboratory data of interest, including 25D, PTH, fibroblast growth factor 23 (FGF23), calcium, phosphorus, hemoglobin, eGFR / creatinine, urinary protein, cholesterol, albumin, C-reactive protein, fibrinogen, homocysteine, and calcium phosphorus product, were captured for 6 months prior to and 6 months after the index date. Lab type, levels, and collection dates were obtained. 25D and PTH levels were collected for up to 1 year before and after the index date.

[0133] result Patients who met the study inclusion criteria were included in the study. Of 1,917 patients, 376 (19.6%) were screened, assessed for study eligibility, and enrolled in the study. Of the enrolled patients, 174 (46.3%) started treatment with an ERC, 55 (14.6%) started treatment with a VDA, and 147 (39.1%) started treatment with a NVD. These patients were assigned to cohorts based on the index criteria (defined in section 3.1). Figure 4 shows the consort diagram of the study, outlining the number of patients and by index dose (converted to weekly dose and presented).

[0134] Within the ERC cohort, 173 (99.4%) patients initiated treatment with 30 mcg per day. Calcitriol was the most common vitamin D therapy prescribed (90.9%) within the VDA cohort. In the NVD cohort, ergocalciferol was prescribed to 66.0% of patients, with 50,000 IU per month being the most commonly prescribed dose.

[0135] The mean (SE) age of the enrolled cohort was 69.5 (13.2) years. The cohort was almost evenly distributed between men (49.2%) and women (50.8%) and was primarily non-Hispanic (88.8%) and white (64.6%). Subjects' mean (SD) height was 167.6 (12.0) cm, weight was 90.8 (25.0) kg, and body mass index (BMI) was 32.8 (15.2). Primary cause of CKD was only documented in 113 (30.2%) subjects, with hypertension (55.6%) and diabetes mellitus (38.9%) being the most common among known causes. eGFR was calculated at baseline using the Modified Diet for Renal Disease (MDRD) equation. More enrolled patients had CKD stage 3 (54.3%) compared with CKD stage 4 (45.7%). The three most common comorbidities were diabetes mellitus (51.6%), hypertension (80.6%), and anemia (40.2%). A total of 71 (18.9%) patients were taking anemia medications concomitantly, but only 14 (3.7%) were taking phosphate binders.

[0136] Age, sex, race, and height were similar across the three index therapy cohorts. The ERC cohort was composed of nearly twice as many Hispanics (15.5%) compared with the VDA (7.3%) and NVD (7.5%) cohorts. On average, those treated with ERC had a higher BMI (34.2) than those treated with VDA (29.4) and NVD (32.4). Furthermore, the primary cause of CKD was similar across cohorts. The majority of patients treated with ERC and VDA were in CKD stage 4, 53.4% ​​and 61.8%, respectively, whereas most patients treated with NVD were in CKD stage 3 (69.4%). Furthermore, the proportion of comorbidities varied across cohorts. Despite many similarities across cohorts, there were subtle differences between treatment arms that may contribute to variability in treatment outcomes. Further details are provided in Table 5. JPEG2025031720000003.jpg198167

[0137] Main analysis The primary analyses assessed key clinical efficacy (25D and PTH) and safety (serum Ca and P) laboratory parameters, and eGFR, in all enrolled patients before and after index treatment initiation. Results were stratified by index cohort (Table 3).

[0138] In 174 ERC patients, baseline 25D and PTH levels averaged 20.3 ± 0.7 (SE) ng / mL and 181 ± 7.4 pg / mL, respectively. ERC treatment increased 25D by 23.7 ± 1.6 ng / mL (p < 0.001) and decreased PTH by 34.1 ± 6.6 pg / mL (p < 0.001), but serum calcium and phosphorus levels were not statistically significant. Furthermore, eGFR was 3.1 ± 0.7 mL / min / 1.73 m 2 decreased (p<0.001).

[0139] In 55 VDA patients, baseline 25D and PTH levels averaged 23.5 ± 1.0 (SE) ng / mL and 156.9 ± 9.7 pg / mL, respectively. VDA treatment increased 25D by 5.5 ± 1.3 ng / mL (p < 0.001) without a statistically significant effect on PTH and serum phosphorus levels. In addition, serum calcium levels increased by 0.2 ± 0.1 mg / dL (p < 0.001) and eGFR decreased by 1.6 ± 0.6 (p < 0.01).

[0140] In 147 NVD patients, baseline 25D and PTH levels averaged 18.8 ± 0.6 (SE) ng / mL and 134.8 ± 6.8 pg / mL, respectively. NVD treatment increased 25D by 9.7 ± 1.5 ng / mL (p < 0.001) without a statistically significant effect on PTH, serum calcium and phosphorus levels. In addition, eGFR decreased by 1.2 ± 0.6 (p < 0.05). The mean weekly dose in NVD patients was 38,392.2 IU.

[0141] On average, patients treated with ERC had the greatest 25D increase during follow-up. Furthermore, ERC was the only treatment that resulted in a significant mean decrease in PTH levels, and only patients treated with ERC had a mean increase in 25D to normal levels (≥30 ng / mL). There was no effect of treatment on calcium or phosphorus levels, except for an increase in serum Ca in patients treated with VDA (Table 6).

[0142] Additional analyses were conducted evaluating efficacy per clinical trial endpoint (NCT01651000). Of 174 patients treated with ERC, 122 (70.1%) achieved a serum 25D ≥ 30 ng / mL and 71 (40.8%) achieved a ≥ 30% decrease in PTH levels. Of 55 patients treated with VDA, 24 (43.6%) achieved a 25D ≥ 30 ng / mL and 12 (21.8%) achieved a ≥ 30% decrease in PTH levels. Of 147 patients treated with NVD, 54 (36.7%) achieved a 25D ≥ 30 ng / mL and 22 (15.0%) achieved a ≥ 30% decrease in PTH levels. Across the cohort, patients treated with ERC had the highest proportion of patients achieving clinical trial endpoints compared with VDA and NVD. Additionally, patients treated with ERC had the lowest proportion of patients with a ≥ 10% increase in PTH. Additional analyses were also performed on whether patients had 25D < 20 ng / mL at baseline and whether they achieved PTH < 70 pg / mL at follow-up (Table 7).

[0143] In addition, an analysis of SHPT progression was performed. SHPT progression was defined as an increase in PTH of at least 10% from baseline. Table 8 shows the results for each cohort. JPEG2025031720000004.jpg33169

[0144] As shown in Table 8, the cohort of patients treated with ERC had the lowest proportion of patients experiencing SHPT progression compared with the other two cohorts.

[0145] Secondary Analyses Percentage change in iPTH analysis-25D quintiles of those treated with ERC A secondary analysis was performed to evaluate changes in PTH in patients treated with ERC. In this analysis, subjects were divided into 5 equal groups based on laboratory 25D levels after treatment initiation. Among patients in quintile 1, there was no statistically significant effect on PTH. Quintiles 2, 3, and 4 achieved mean PTH reductions of 19.3%, 14.5%, and 26.6%, respectively. A mean PTH reduction of >30% was not achieved until quintile 5, where 25D increased to a mean of 79.1 ± (2.1) ng / mL (Table 9).

[0146] Additional secondary analyses were performed to evaluate changes in PTH across the cohort; as well as laboratory measures of safety (serum Ca and P), and the clinical endpoint of >30% PTH decline. Results were split by index therapy cohort. In this analysis, subjects were divided into groups based on index therapy and 25D achievement level. A mean PTH decline of >30% was not achieved until 25D increased to >60 ng / mL. Only 0 (0%) patients treated with VDA and 2 (1.3%) patients treated with NVD achieved 25D >60 ng / mL, whereas 41 (23.6%) patients treated with ERC achieved 25D >60 ng / mL. Across all 25D achievement levels, treatment with ERC did not affect serum calcium or phosphate (Table 10).

[0147] The key points of this test are: On average, ERC was the only treatment that increased 25D to normal levels (≥30ng / mL). In almost all subgroup analyses, treatment with ERC did not affect key safety markers (serum calcium and phosphorus). The highest proportion of subjects treated with ERC in the real-world setting achieved a ≥ 30ng / mL and ≥ 30% reduction in iPTH during follow-up. When iPTH reduction was assessed at the level of 25D achieved, a mean iPTH reduction of ≥ 30% was not achieved until 25D increased to ≥ 60ng / mL. Despite differences in patient demographic and clinical characteristics at baseline, real-world patients had similar clinical efficacy and safety outcomes when compared with clinical trial results. However, differences in overall changes in 25D in the ERC cohort may be due to dose escalation or the use of concomitant medications. · When evaluating pivotal clinical trial endpoint treatments with ERCs in the real world, similar results are seen compared to clinical trials. · 122 (70.1%) patients treated with ERC achieved >30ng / mL at follow-up compared with 80%-83% in clinical trials. Seventy-one (40.8%) patients treated with ERC achieved a >30% reduction in PTH at follow-up, compared with 33%-34%. Variations in baseline levels, dosing patterns, and concomitant medications may lead to differences in achievement of clinical trial endpoints. Adherence to the recommended dose titration of 60 mcg / day may result in a further increase in 25D and a decrease in PTH levels.

[0148] conclusion This chart review demonstrates that treatment with ERC in the real-world setting produced similar clinical efficacy and safety outcomes to the clinical trial, albeit in a more severe population and at lower levels of dosing. Furthermore, similar rates of achievement of the clinical trial endpoints were produced in the real-world setting. Although the rate of dose escalation is lower in the real-world setting, increasing the dose of ERC may further increase 25D and decrease PTH levels in the real-world setting. Overall, this study provides strong evidence that the clinical efficacy and safety of ERC treatment are maintained in the real-world setting.

[0149] References

[0150] Agarwal R,Georgianos PI.Con:Nutritional vitamin D replacement in chronic kidney disease and end-stage renal disease.Nephrol Dial Transplant 2016 31:706-713.

[0151] Ennis JL,Worcester EM,Coe FL et al.Current recommended 25-hydroxyvitamin D targets for chronic kidney disease management may be too low.J Nephrol.2016 29: 63-70.

[0152] Helvig CF,Cuerrier D,Hosfield CM et al.Dysregulation of renal vitamin D metabolism in the uremic rat.Kidney Int.2010 78:463-472.

[0153] Holick MF.Environmental factors that influence the cutaneous production of vitamin D.Am J Clin Nutr.1995 61: 638S-645S.

[0154] Holick MF,Binkley NC,Bischoff-Ferrari HA,et al.Evaluation,treatment,and prevention of vitamin D deficiency:an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab.2011;96:1911-1930.

[0155] Kalantar-Zadeh K,Kovesdy CP.Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease.Clin J Am Soc Nephrol.2009 4: 1529-1539.

[0156] Kidney Disease:Improving Global Outcomes(KDIGO)CKD-MBD Work Group.KDIGO clinical practice guideline for diagnosis,evaluation, prevention,and treatment of chronic kidney disease-mineral and bone disorder(CKD-MBD).Kidney Int.2009 76:S1-S130

[0157] Kidney Disease Improving Global Outcomes(KDIGO)2017 clinical practice guideline update for the diagnosis,evaluation,prevention and treatment of chronic kidney disease-mineral and bone disorder(CKD-MBD).Kidney Int Suppl.2017;7:S1-S59.

[0158] Levin A,Bakris GL,Molitch M et al.Prevalence of abnormal serum vitamin D,PTH,calcium,and phosphorus in patients with chronic kidney disease:results of the study to evaluate early kidney disease.Kidney Int.2007 71:31-38.

[0159] National Kidney Foundation.K / DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.Am J Kidney Dis.2003 42: S1-S202.

[0160] Souberbielle J, Body J, Lappe JM et al.Vitamin D and musculoskeletal health,cardiovascular disease,autoimmunity and cancer:Recommendations for clinical practice.Autoimmun Rev.2010 9:709-715.

[0161] Sprague,SM et al.Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease.Am J Nephrol 2016 44(4)316-325.

[0162] Sprague, SM et al.Extended-release calcifediol for secondary hyperparathyroidism in stage 3-4 chronic kidney disease.Expert Rev Endocrinol Metab.2017;12(5):289-301.

[0163] The foregoing description has been given for clarity of understanding only, and no unnecessary limitations should be construed therefrom, since modifications within the scope of the invention may be apparent to those skilled in the art.

[0164] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are understood to mean the inclusion of a stated integer or step or group of integers or steps but not to the exclusion of any other integer or step or group of integers or steps.

[0165] Throughout this specification, when a composition is described as comprising components or materials, it is understood that the composition may consist essentially of or consist of any combination of the recited components or materials, unless otherwise indicated. Similarly, when a method is described as including particular steps, it is contemplated that the method may consist essentially of or consist of any combination of the recited steps, unless otherwise indicated. The inventions illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0166] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or can be performed using electronic devices or automation. Although the process has been described with reference to certain embodiments, those skilled in the art will readily understand that other methods of performing the acts associated with the methods can be used. For example, unless otherwise stated, the order of various steps can be changed without departing from the scope or spirit of the method. Furthermore, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0167] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between this disclosure and the incorporated patents, publications, and references, this disclosure shall control.

Claims

1. 1. A method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising effectively administering 25-hydroxyvitamin D to increase and maintain said patient's serum total 25-hydroxyvitamin D to a concentration of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, or at least 60 ng / mL, thereby preventing, halting, or reversing SHPT progression in said patient.

2. 1. A method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising effectively administering sustained release 25-hydroxyvitamin D to increase and maintain said patient's serum total 25-hydroxyvitamin D to a concentration of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL, or at least 60 ng / mL, thereby preventing, halting, or reversing SHPT progression in said patient.

3. 1. A method of preventing, halting, or reversing SHPT progression in a patient population, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising effectively administering 25-hydroxyvitamin D to increase and maintain said patient's serum total 25-hydroxyvitamin D to an average concentration of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL or at least 60 ng / mL, thereby preventing, halting, or reversing SHPT progression in said patient population, wherein the percentage of subjects experiencing SHPT progression is less than 30%, 25%, 20%, 15%, 10%, or 9.7% or less, or less than 3%, or 2.8% or less.

4. 1. A method of preventing, halting, or reversing SHPT progression in a patient population, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising effectively administering sustained release 25-hydroxyvitamin D to increase and maintain said patient's serum total 25-hydroxyvitamin D to an average concentration of greater than 50 ng / mL, optionally at least 50.8 ng / mL, optionally at least 51 ng / mL or at least 60 ng / mL, thereby preventing, halting, or reversing SHPT progression in said patient population, wherein the percentage of subjects experiencing SHPT progression is less than 30%, 25%, 20%, 15%, 10%, or 9.7% or less, or less than 3%, or 2.8% or less.

5. 1. A method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, to an extent greater than that achieved with a vitamin D analog (VDA) or nutritional vitamin D (NVD), hydroferol, or any combination thereof, optionally to an extent at least 2-fold greater than that achieved with a VDA, NVD, hydroferol, or any combination thereof; a. increasing and maintaining serum total 25-hydroxyvitamin D in a patient; b. reducing serum iPTH in said patient; or c. A combination thereof.

6. 1. A method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, to an extent greater than that achieved with a vitamin D analog (VDA) or nutritional vitamin D (NVD), hydroferol, or any combination thereof, optionally to an extent at least 2-fold greater than that achieved with a VDA, NVD, hydroferol, or any combination thereof; a. increasing and maintaining serum total 25-hydroxyvitamin D in a patient; b. reducing serum iPTH in said patient; or c. Combinations thereof, administering to said patient sustained release 25-hydroxyvitamin D.

7. 7. The method of claim 6, wherein serum total 25-hydroxyvitamin D is increased by more than 20 ng / mL compared to pre-treatment levels.

8. 8. The method of claim 6 or 7, wherein serum iPTH is reduced by at least 10 pg / mL compared to pre-treatment levels.

9. 9. The method of claim 8, wherein serum iPTH is reduced by at least 20 pg / mL compared to pre-treatment levels.

10. 10. The method of claim 9, wherein serum iPTH is reduced by at least 30 pg / mL compared to pre-treatment levels.

11. 11. The method of claim 10, wherein serum iPTH is reduced by more than 30% compared to pre-treatment levels.

12. 1. A method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising: a. increasing and maintaining the patient's serum total 25-hydroxyvitamin D to greater than 20 ng / mL compared to pre-treatment levels; b. reducing serum iPTH in said patient by at least 30% compared to pre-treatment levels; or c. A combination thereof.

13. 1. A method of preventing, halting, or reversing SHPT progression in a patient, defined as an increase in plasma iPTH of >10% from a pre-treatment baseline, comprising: a. increasing and maintaining the patient's serum total 25-hydroxyvitamin D to greater than 20 ng / mL compared to pre-treatment levels; b. reducing serum iPTH in said patient by at least 30% compared to pre-treatment levels; or c. Combinations thereof, administering to said patient sustained release 25-hydroxyvitamin D.

14. 14. The method of any one of claims 1 to 13, wherein the prevention, halting, or reversal of SHPT progression is achieved for 26 weeks or more.

15. 1. A method of treating a disease, condition, or disorder associated with an increase in iPTH from the patient's baseline in a patient in need of such treatment, comprising administering 25-hydroxyvitamin D to effectively increase and maintain said patient's serum total 25-hydroxyvitamin D in the range of about 50 to about 300 ng / mL, optionally about 60 ng / mL to about 300 ng / mL, during chronic administration, thereby treating said disease, condition, or disorder.

16. 1. A method of treating a disease, condition, or disorder associated with an increase in iPTH from the patient's baseline in a patient in need of such treatment, comprising administering sustained release 25-hydroxyvitamin D to effectively increase and maintain said patient's serum total 25-hydroxyvitamin D in the range of about 50 to about 300 ng / mL, optionally about 60 ng / mL to about 300 ng / mL, during chronic administration, thereby treating said disease, condition, or disorder.

17. 1. A method of attenuating SHPT progression in a patient in need of treatment thereof, comprising administering 25-hydroxyvitamin D at a dosage ranging from 100 to 900 μg per week to effectively gradually increase and thereafter maintain said patient's serum total 25-hydroxyvitamin D level to a concentration ranging from about 50 to 300 ng / mL, optionally from about 60 ng / mL to about 300 ng / mL, thereby attenuating the progression of SHPT progression in said patient.

18. 1. A method of attenuating progression of SHPT in a patient in need of treatment thereof, comprising administering sustained release 25-hydroxyvitamin D at a dosage ranging from 100 to 900 μg per week to effectively gradually increase and thereafter maintain said patient's serum total 25-hydroxyvitamin D level to a concentration ranging from about 50 to 300 ng / mL, optionally from about 60 ng / mL to about 300 ng / mL, thereby attenuating progression of SHPT in said patient.

19. 1. A method of treating a patient by (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to greater than 20 ng / mL, (b) reducing the patient's serum iPTH to at least 30 pg / mL, or (c) any combination thereof, the method comprising administering to the patient an amount of 25-hydroxyvitamin D for a treatment period of at least six months.

20. 1. A method of treating a patient by (a) increasing and maintaining the patient's serum total 25-hydroxyvitamin D to greater than 20 ng / mL, (b) reducing the patient's serum iPTH to at least 30 pg / mL, or (c) any combination thereof, the method comprising administering to the patient an amount of sustained release 25-hydroxyvitamin D for a treatment period of at least six months.

21. The method of any one of claims 1 to 20, wherein serum calcium and phosphorus levels do not change in the patient during treatment.

22. 22. The method of any one of claims 1 to 21, comprising increasing 25-hydroxyvitamin D to maintain said patient's serum total 25-hydroxyvitamin D level at a concentration in the range of greater than 50 ng / mL to about 300 ng / mL, optionally from about 60 ng / mL to about 300 ng / mL.

23. 23. The method of claim 22, comprising increasing 25-hydroxyvitamin D to maintain said patient's serum total 25-hydroxyvitamin D level at a concentration ranging from greater than 50 ng / mL to about 200 ng / mL, optionally from about 60 ng / mL to about 200 ng / mL.

24. 24. The method of claim 23, comprising increasing 25-hydroxyvitamin D to maintain said patient's serum total 25-hydroxyvitamin D level at a concentration ranging from greater than 50 ng / mL to about 100 ng / mL, optionally from about 60 ng / mL to about 100 ng / mL.

25. 25. The method of any one of claims 1-24, wherein the effective administration of 25-hydroxyvitamin D comprises avoiding a significant increase in the patient's corrected serum calcium level compared to a pre-treatment baseline.

26. 26. The method of any one of claims 1-25, wherein the effective administration of 25-hydroxyvitamin D comprises avoiding a significant increase in the patient's serum phosphorus levels compared to a pre-treatment baseline.

27. 27. The method of any one of claims 1-26, wherein the effective administration of 25-hydroxyvitamin D comprises avoiding a significant increase in serum FGF23 levels in the patient compared to a pre-treatment baseline.

28. 28. The method of any one of claims 1-27, wherein the effective administration of 25-hydroxyvitamin D comprises providing an average daily increase in serum total 25-hydroxyvitamin D of 3 ng / mL or less during an increase in serum total 25-hydroxyvitamin D.

29. 29. The method of any one of claims 1-28, wherein the effective administration of 25-hydroxyvitamin D comprises providing an average daily increase in serum total 25-hydroxyvitamin D of at least 0.2 ng / mL during the increase in serum total 25-hydroxyvitamin D.

30. 30. The method of any one of claims 1-29, wherein the effective administration of 25-hydroxyvitamin D comprises increasing serum total 25-hydroxyvitamin D to a steady state level in the range of about 50 or about 60 to about 300 ng / mL, or about 50 or about 60 to about 200 ng / mL, or about 50 or about 60 to about 100 ng / mL, or greater than 50 or 60 to about 300 ng / mL, or greater than 50 or 60 to about 200 ng / mL, or greater than 50 or 60 to about 100 ng / mL, over a period of at least 8 weeks, or at least 10 weeks, or at least 12 weeks, or at least 14 weeks.

31. 31. The method of any one of claims 1-30, wherein the effective administration of 25-hydroxyvitamin D comprises increasing the patient's serum total 1,25-dihydroxyvitamin D to a steady state level of at least 40 pg / mL, or at least 45 pg / mL.

32. 32. The method of any one of claims 1-31, wherein the effective administration of 25-hydroxyvitamin D comprises increasing serum total 1,25-dihydroxyvitamin D to a steady state level of 62 pg / mL or less.

33. 33. The method of any one of claims 1-32, wherein the patient is vitamin D deficient, having less than 30 ng / mL serum total 25-hydroxyvitamin D at the start of therapy.

34. 34. The method of claim 33, wherein the patient has a serum total 25-hydroxyvitamin D of at least 10 ng / mL at the start of therapy.

35. 33. The method of any one of claims 1-32, wherein the patient has serum total 25-hydroxyvitamin D greater than or about 30 ng / mL at the start of therapy.

36. 36. The method of claim 35, wherein the patient has greater than or about 40 ng / mL serum total 25-hydroxyvitamin D at the start of therapy.

37. 37. The method of any one of claims 1-36, wherein the amount of 25-hydroxyvitamin D administered is effective to achieve a mean total serum 25-hydroxyvitamin D level in the patient, or the population, of up to about 300 ng / mL, or up to about 200 ng / mL, or up to about 100 ng / mL, or up to about 93 ng / mL, or up to about 92.5 ng / mL, or up to about 90 ng / mL, or up to about 85 ng / mL, or up to about 80 ng / mL, or up to about 70 ng / mL, or up to about 69 ng / mL, or up to 68.9 ng / mL.

38. 38. The method of any one of claims 1 to 37, wherein the patient has CKD stage 3-5, or stage 3-4, or stage 5.

39. The method of any one of claims 1 to 38, wherein the patient has CKD stage 3 or 4.

40. The method of any one of claims 1 to 39, wherein the patient has CKD stage 5.

41. The method according to any one of claims 1 to 40, wherein the patient is also undergoing treatment with hemodialysis.

42. The administration of 25-hydroxyvitamin D 3 25-hydroxyvitamin D 3 or consisting essentially of the administration of 25-hydroxyvitamin D 3 42. The method of any one of claims 1 to 41, comprising administering

43. 43. The method of any one of claims 1 to 42, wherein the administration of 25-hydroxyvitamin D comprises modified release administration.

44. 44. The method of any one of claims 1 to 43, wherein the administration of 25-hydroxyvitamin D comprises sustained release administration.

45. 45. The method of any one of claims 1 to 44, wherein the administration of 25-hydroxyvitamin D comprises oral administration.

46. 46. ​​The method of any one of claims 1-45, wherein administering 25-hydroxyvitamin D comprises administering 25-hydroxyvitamin D intravenously over an extended period of time, optionally for at least 1 hour, optionally for up to 5 hours.

47. 47. The method of any one of claims 1 to 46, wherein the administration of 25-hydroxyvitamin D comprises avoiding substantial induction of CYP24A1, optionally characterized by a VMR of 5 or less, or 4.8 or less.

48. 48. The method of any one of claims 1 to 47, wherein the 25-hydroxyvitamin D is administered daily or less frequently.

49. 49. The method of any one of claims 1 to 48, wherein the 25-hydroxyvitamin D is administered daily.

50. 50. The method of any one of claims 1 to 49, wherein the 25-hydroxyvitamin D is administered twice a week.

51. 51. The method of any one of claims 1 to 50, wherein the 25-hydroxyvitamin D is administered three times per week.

52. 52. The method of any one of claims 1-51, wherein the 25-hydroxyvitamin D is administered weekly.

53. 53. The method of any one of claims 1-52, wherein the 25-hydroxyvitamin D is administered in a unit dosage form containing between 30 μg and 600 μg of 25-hydroxyvitamin D.

54. 54. The method of any one of claims 1 to 53, wherein the unit dose form comprises 30 μg of 25-hydroxyvitamin D.

55. 55. The method of any one of claims 1 to 54, wherein the unit dose form contains 60 μg of 25-hydroxyvitamin D.

56. 56. The method of any one of claims 1 to 55, wherein the unit dose form contains 90 μg of 25-hydroxyvitamin D.

57. 57. The method of any one of claims 1 to 56, wherein the unit dose form contains 200 μg of 25-hydroxyvitamin D.

58. 58. The method of any one of claims 1-57, comprising administering 25-hydroxyvitamin D in the range of about 100 μg to about 900 μg per week, or about 300 μg to about 900 μg per week, optionally 600 μg per week.

59. 59. The method of any one of claims 1-58, comprising administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight at the start of therapy.

60. 60. The method of claim 59, wherein said dose is or corresponds to a daily dose of from about 0.1 mcg / kg of said patient's body weight at the initiation of therapy to about 1 mcg / kg of said patient's body weight at the initiation of therapy, optionally from about 0.15 mcg / kg of said patient's body weight at the initiation of therapy to about 0.85 mcg / kg of said patient's body weight at the initiation of therapy.

61. 61. The method of claim 60, wherein said daily dose is from about 0.4mcg / kg to about 0.8mcg / kg of said patient's body weight at the start of therapy.

62. 62. The method of any one of claims 59-61, comprising administering to the patient an initial dose of 60mcg if the patient weighs 140kg or more at the start.

63. 63. The method of any one of claims 1 to 62, comprising administering a divided weekly dose of 25-hydroxyvitamin D in two or three doses per week, optionally three times per week during dialysis treatment.

64. 64. The method of any one of claims 1 to 63, comprising reducing the blood level of a bone resorption marker in the patient.

65. 65. The method of claim 64, wherein the bone resorption marker is one or more markers selected from serum total alkaline phosphatase, BSAP, CTX-1, P1NP and FGF-23.

66. 66. The method of claim 64 or 65, wherein the decrease is to within the normal reference range of the marker.

67. 67. The method of any one of claims 64 to 66, wherein the decrease is at least about 10%, or at least about 20%, or at least about 30%.

68. 68. The method of any one of claims 1-67, wherein the SHPT progression is based on 26 weeks of treatment compared to (a) untreated patients, or (b) patients treated with active vitamin D therapy (optionally calcitriol, paricalcitol, or doxercalciferol), (c) patients treated with nutritional vitamin D (ergocalciferol and / or cholecalciferol), or (d) patients treated with hydroferol.

69. 1. A method of treating SHPT in a patient having CKD comprising administering to the patient a dose of 25-hydroxyvitamin D selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration, or based on the patient's weight and a desired increase in serum 25-hydroxyvitamin D.

70. 70. The method of claim 69, comprising selecting a dose for the patient to provide a post-treatment serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml.

71. 70. The method of claim 69, comprising selecting a dose for the patient to provide a steady state serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml.

72. 72. The method of any one of claims 69 to 71, wherein the administration is by sustained release oral administration.

73. 73. The method of any one of claims 69 to 72, wherein the dose is a daily dose.

74. 74. The method of claim 72 or 73, wherein the dose (D) in mcg is a daily dose or an amount equivalent to a daily dose selected by the relationship D=(RxW) / F as a function of the patient's weight at the start of therapy in kilograms (W) and the desired increase in serum 25-hydroxyvitamin D in ng / ml (R), including a scaling factor (F), where F is in the range of about 50 to about 80, or about 55 to about 80, or about 65 to about 75, or about 68 to about 72, or about 69 to about 71, or about 70.

75. 74. The method of claim 72 or 73, wherein the dose (D) in mcg is a daily dose or equivalent amount to a daily dose selected as a function of the patient's weight at the start of therapy in kilograms (W) and the desired rise in serum 25-hydroxyvitamin D in ng / ml (R), including a scaling factor (F), according to the relationship D=(RxW) / F, where F is based on a sub-factor f and a further adjustment Y based on the patient's weight W, such that F=f-(YxW), where f is in the range of about 60 to about 80, or about 65 to about 75, or about 68 to about 72, or about 69 to about 71, or about 70, and Y is in the range of 0.01 to 0.

1.

76. 76. The method according to any one of claims 74 to 75, wherein the patient's weight W is in the range of 50 kg to 180 kg.

77. 77. The method of any one of claims 69 to 76, wherein the patient has stage 3 or stage 4 CKD.

78. 78. The method of any one of claims 69-77, wherein the patient's dose is selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration to provide a post-treatment serum 25-hydroxyvitamin D concentration of at least 50 ng / ml, or at least 50.8 ng / ml, or at least 51 ng / ml, or at least 60 ng / ml.

79. 79. The method of any one of claims 69-78, wherein the method further provides at least a 30% reduction in the patient's plasma iPTH concentration compared to a pre-treatment baseline.

80. 1. A method of treating SHPT in a patient having CKD, comprising administering to the patient a dose of sustained release 25-hydroxyvitamin D selected based on the patient's weight and baseline serum 25-hydroxyvitamin D concentration, or based on the patient's weight and a desired increase in serum 25-hydroxyvitamin D.

81. 1. A pharmaceutical composition comprising 25-hydroxyvitamin D and a pharma- ceutically acceptable excipient, said composition being administered to treat a disease or condition associated with an increase in iPTH from baseline, said administration increasing and maintaining a patient's serum level of 25-hydroxyvitamin D between about 50-300 ng / mL or between about 60-300 ng / ml during chronic administration of said composition.

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