Hypoparathyroidism Treatment

Abstract

The present invention relates to a PTH compound for use in the treatment of hypoparathyroidism, wherein the treatment comprises single daily administrations of the PTH compound to a patient and titrating the patient off of standard of care within four weeks from the time the first dose of the PTH compound was administered.

Claims

1. A method of treating or controlling a patient suffering from hypoparathyroidism, wherein the method comprises the step of administering to the patient single daily administrations of a PTH compound and titrating the patient off a standard of care within four weeks from the time the first dose of the PTH compound was administered.

2. The method of claim 1, wherein the patient is titrated off the standard of care within three weeks from the time the first dose of the PTH compound is administered.

3. The method of claim 1, wherein the patient is titrated off the standard of care within two weeks from the time the first dose of the PTH compound is administered.

4. The method of claim 1, wherein the single daily dose of the PTH compound is below 31 μg/day.

5. The method of claim 1, wherein the single daily dose of the PTH compound is selected from 15 μg/day, 18 μg/day and 21 μg/day.

6. The method of claim 1, wherein the patient is a human patient.

7. The method of claim 1, wherein administration is by subcutaneous injection.

8. The method of claim 1, wherein administration is with a pen injector.

9. The method of claim 1, wherein titrating the patient off the standard of care is performed according to the following the titration scheme (i) Visit 1: Decrease active vitamin D dose by 33-50%; (ii) Day 3-4: Discontinue active vitamin D; (iii) Day 6-7: Decrease calcium supplementation by 50%; (iv) Day 9-10: If daily nutritional calcium exceeds 750 mg/day, discontinue calcium supplements; if daily nutritional calcium intake is <750 mg/day, a calcium supplement to achieve the RDA can be maintained at the discretion of the physician.

10. The method of claim 1, wherein titrating the patient off the standard of care is performed according to the following the titration scheme (i) Visit 1: Decrease active vitamin D dose by 33-50% (ii) Day 3-4: Discontinue active vitamin D; (iii) Day 6-7: If taking calcium ≤2000 mg/day, decrease calcium by ≥50% (≥400 mg/day); if on calcium >2000 mg/day, decrease calcium by ≥800 mg/day; (iv) Day 9-10: If on calcium ≤2000 mg/day discontinue; if dietary calcium <750 mg/day maintain calcium at 400 or 500 mg/day or decrease calcium to 500 mg/day; if on calcium >2000 mg/day, decrease calcium by ≥800 mg/day.

11. The method of claim 1, wherein 4 weeks after administration of the first dose of the PTH compound a statistically significant change in the Short Form-36 Physical Component Summary, in the SF-36 Mental Component Summary or both the SF-36 PCS and SF-36 MCS is achieved.

12. The method of claim 1, wherein the PTH compound is a conjugate or a pharmaceutically acceptable salt thereof comprising at least one moiety -D conjugated via at least one moiety -L.sup.1-L.sup.2- to at least one moiety Z, wherein the linkage between -D and -L.sup.1- is reversible and wherein a moiety -L.sup.2- is conjugated to Z, wherein each -D is independently a PTH moiety; each -L.sup.1- is independently a reversible linker moiety; each -L.sup.2- is independently a single chemical bond or a spacer moiety; and each Z is independently a polymeric moiety or a C.sub.8-24 alkyl moiety.

13. The method of claim 1, wherein the PTH compound comprises a PTH moiety having the sequence of SEQ ID NO:51.

14. The method of claim 1, wherein the PTH compound is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof ##STR00042## wherein -D is a PTH moiety; -L.sup.1- is a linker moiety reversibly and covalently connected to the PTH moiety -D through a functional group of PTH; -L.sup.2- is a single chemical bond or a spacer moiety; —Z is a polymer moiety or a C.sub.8-24 alkyl moiety; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; and y is an integer selected from the group consisting of 2, 3, 4 and 5.

15. The method of claim 12, wherein the moiety -L.sup.1-L.sup.2- is selected from the group consisting of ##STR00043## wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a PTH moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to —Z.

16. The method of claim 12, wherein the PTH compound is of formula (IIf-i): ##STR00044## wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a PTH moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to a moiety ##STR00045## wherein m and p are independently an integer ranging from and including 400 to 500.

17. The method of claim 1, wherein the PTH compound comprises a PTH moiety having the sequence SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 or SEQ ID NO:115.

18. The method of claim 12, wherein —Z is a PEG-based polymer.

19. The method of claim 12, wherein —Z is a branched PEG-based polymer.

Description

EXAMPLE 1

[0531] Human participants were randomly assigned to one of four groups: three groups received fixed doses of compound 1 and one group received placebo. Compound 1 or placebo were administered as a subcutaneous injection using a pre-filled injection pen. Neither trial participants nor their doctors knew who were assigned to each group. After the four weeks, participants were eligible to continue in the trial as part of a long-term extension study. During the extension, all participants received compound 1, with the dose adjusted to their individual needs.

[0532] The double-blind, placebo-controlled, parallel group treatment period of this trial was designed to enroll approximately 55 male and female adults with either postsurgical HP or autoimmune, genetic, or idiopathic HP for at least 26 weeks, from up to approximately 40 sites worldwide. ClinicalTrials.gov Identifier: NCT04009291 Subjects were randomized into 4 treatment groups (1:1:1:1): [0533] Compound 1 15 μg/day* [0534] Compound 1 18 μg/day* [0535] Compound 1 21 μg/day* [0536] Placebo for compound 1 (excipients solution)
(*Dose of compound 1 refers to dose of PTH(1-34) administered measured in PTH equivalents)

[0537] To maintain blinding, the placebo group were sub-randomized into 3 groups (1:1:1) to mimic doses of 15, 18, and 21 μg/day.

[0538] Subjects remained on the same dose of study drug throughout the 4-week Blinded Treatment Period. Following successful completion of the Blinded Treatment Period, subjects entered open-label Extension Period at which time all subjects received compound 1.

[0539] The entire study was designed such that each subject's participation may last up to 58 weeks plus a screening period of up to approximately 4 weeks. [0540] Screening Period (supplement optimization): Up to approximately 4 weeks [0541] Blinded Treatment Period (compound 1 dose stable with SOC optimization): 4 weeks [0542] Extension Period (open-label compound 1 treatment): 54 weeks, with up to an initial 14 weeks of compound 1 titration and SOC optimization, followed by approximately 40 weeks of stable dosing

[0543] Titration Scheme (Assuming Maintenance of a Normal Serum Calcium Level) [0544] Visit 1: Decrease active vitamin D dose by 33-50% (eg, skip 2.sup.nd dose of the day if taking BID, skip last dose of the day if taking TID, or reduce once daily dose of alphacalcidol ≥1.0 μg by ≥0.5 μg); [0545] Day 3-4: Discontinue active vitamin D; [0546] Day 6-7: If on active vitamin D, discontinue active vitamin D; if off active vitamin D, and on calcium ≤2000 mg/day, decrease calcium by ≥50% (≥400 mg/day) and if on calcium >2000 mg/day, decrease calcium by ≥800 mg/day; [0547] Day 9-10: If on active vitamin D, discontinue active vitamin D; if off active vitamin D, and on calcium ≤2000 mg/day, discontinue* or decrease calcium to ≤500 mg/day (*if dietary calcium <750 mg/day, maintain calcium at 400 or 500 mg/day); if on calcium >2000 mg/day, decrease calcium by ≥800 mg/day

[0548] Results

[0549] Preliminary data on first 8 subjects completing 4 weeks follow-up in open label extension demonstrated that all subjects are completely off standard of care with 8 of 8 subjects no longer require active vitamin D. 7/8 subjects no longer required calcium supplementation. One subject continued taking a daily dietary supplemental dose of <500 mg calcium in order to reach the recommended daily intake for calcium.

[0550] Full data, 4-weeks fixed dose period: All 59 subjects from the trial completed an initial fixed dose 4-week period, where optimization of doses was not allowed. Patients randomized to compound 1 were able to discontinue oral active vitamin D. Similarly, these patients were able to stop therapeutic doses of oral calcium, and oral calcium intake was reduced from a mean of 2213 mg/day at baseline to a mean of 560 mg/day after 4 weeks of dosing with compound 1. In contrast, patients receiving placebo could not discontinue standard of care, and had a reduction of oral active vitamin D from 1.1 ug/day at baseline to 0.9 ug/day at 4 weeks, and reduced oral calcium supplements from 1685 mg/day at baseline to 1368 mg/day at 4 weeks.

[0551] Full data, 26 weeks: All 59 subjects completed the initial 4-week period and continued in the open label extension (OLE); 58 subjects continued in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). Patients treated with compound 1 continued to reduce oral calcium intake, which dropped to a mean of 294 mg/day at week 26. Furthermore, mean 24-hour uCa decreased from a baseline mean of 415 mg/24 h to 178 mg/24 h by Week 26 (n=44) while maintaining normal sCa and reducing sP and CaxP. Importanly, no subjects had PTH treatment-emergent adverse events related to hyper- or hypocalcemia leading to ER/urgent care visit and/or hospitalization.

EXAMPLE 2

[0552] Administration of compound 1 to the human participants described in example 1 resulted in a statistically significant improvement compared to placebo in a double blinded trial for the SF-36. The SF-36 survey consists of 36 questions and the results are summarized in a Physical Component Summary (PCS) and Mental Component Summary (MCS). At baseline, all subjects had lower-than-average SF-36 scores. Statistically significant and clinically meaningful improvements in PCS and MCS were noted in the 4 weeks double blinded controlled part of the phase 2 trial. For the PCS score, using a normative scoring system with a score of 50 as the norm for the general population and an ANCOVA model, subjects receiving compound 1 demonstrated a mean 4.5 point increase compared to a mean -0.69 point decrease for placebo. The placebo adjusted mean difference is 5.2 points with a p-value of 0.013. The minimally important difference for PCS is 2 points.

[0553] For the Mental Component Summary score, subjects receiving compound 1 demonstrated a mean 6.0-point increase compared to a mean -3.8 point decrease for placebo. The placebo adjusted difference in mean of 9.8 points with a p-value of 0.0003. The minimally important difference for MCS is 3 points.

[0554] Full data, 26 weeks: All 59 subjects completed the initial 4-week period and continued in the open label extension (OLE); 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for patients receiving compound 1 and placebo subjects switching to compound 1. Details are shown in Table 1. Compound 1 continued to be well-tolerated with no treatment-related serious or severe adverse events.

TABLE-US-00002 TABLE 1 Mean scores for all SF-36 domains Placebo Placebo Switch to Compound 1 All compound 1 (n = 15) compound 1 (n = 44) (n = 59) SF-36 Week (n = 15) Week 6 6 domain Baseline 4 6 Months Baseline 4 Months Baseline Months PF 45 (11) 46 (14) 51 (7) 46 (9)  51 (6) 52 (5) 46 (10) 51 (6) RP 42 (10) 42 (14)  49 (11) 42 (10) 49 (8) 51 (6) 42 (10) 50 (7) BP 43 (11) 40 (16)  46 (10) 46 (10) 49 (8) 51 (9) 45 (10) 50 (9) GH 44 (10) 47 (11) 50 (7) 43 (10) 47 (8) 51 (9) 43 (10) 51 (8) VT 44 (12) 43 (12)  52 (10) 42 (11) 49 (9) 53 (8) 43 (11) 53 (8) SF 44 (11) 41 (15) 53 (5) 42 (10) 50 (8) 52 (6) 43 (10) 52 (6) RE 45 (12) 39 (16) 51 (7) 42 (13)  49 (10) 50 (8) 43 (13) 50 (7) MH 47 (9)  47 (11) 55 (5) 46 (9)  51 (8) 51 (8) 46 (9)  52 (7) PCS 43 (12) 44 (14) 48 (8) 45 (10) 49 (7) 51 (7) 44 (11) 50 (8) MCS 46 (10) 43 (12) 54 (6) 43 (11) 50 (9) 51 (8) 44 (11) 52 (8) PF = physical functioning; RP = physical role functioning; BP = bodily pain; GH = general health perceptions; VT = vitality; SF = social role functioning; RE = emotional role functioning; MH = mental health; PCS = Physical Component Summary; MCS = Mental Component Summary

EXAMPLE 3

[0555] All 59 subjects completed the initial 4-week period and continued in the open label extension (OLE); 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). At baseline, mean BMD Z-scores at lumbar spine, femoral neck and total hip were elevated due to lack of bone turnover. With treatment with compound 1, BMD mean Z-score trended toward normalization at week 26, as shown in Table 2.

TABLE-US-00003 TABLE 2 Bone mineral density measurements Week 26 change from N = 44 Baseline Week 26 baseline Lumbar spine L1-L4 Mean BMD Z-score 1.6 0.9 −0.7 Femoral neck Mean BMD Z-score 1.2 0.7 −0.5 Total hip Mean BMD Z-score 1.0 0.6 −0.5 ⅓ radius Mean BMD Z-score 0.4 0.4  0.0

Abbreviations

[0556] BID bis in die, i.e. twice a day [0557] HP hypoparathyroidism [0558] PTH parathyroid hormone [0559] RDA recommended daily/dietary allowance [0560] sCA serum calcium [0561] SOC standard-of-care [0562] TID ter in die, i.e three times a day