THERAPEUTIC USES OF DULAGLUTIDE

Abstract

The present invention relates to methods of using dulaglutide for the treatment of chronic kidney disease in patients having moderate to late stage chronic kidney disease.

Claims

1. A method of treating CKD in a patient, comprising: a) identifying a patient having either: i) eGFR between 15-59 mL/min/1.73 m.sup.2; or ii) UACR greater than 30 mg/g and eGFR between 60-89 mL/min/1.73 m.sup.2; b) administering said patient an effective amount of dulaglutide once a week; and c) continuing said once a week administration for at least 6 months; and wherein said administration results in attenuation in the progression of the patient's CKD.

2. The method of claim 1 wherein said attenuation in the progression of the patient's CKD is not entirely dependent on improvements to the patient's glycemic control.

3. A method of treating T2DM and decreasing the rate of loss of eGFR in a patient having T2DM and CKD, comprising: a) identifying a patient having T2DM and either: i) eGFR between 15-59 mL/min/1.73 m.sup.2; or ii) UACR greater than 30 mg/g and eGFR between 60-89 mL/min/1.73 m.sup.2; b) administering said patient an effective amount of dulaglutide once a week; and continuing said once a week administration for at least 6 months.

4. The method of claim 3 wherein the decreased rate of loss of eGFR is not entirely dependent on improvements to the patient's glycemic control.

5. The method of claim 1 wherein the patient's CKD is not caused by T2DM.

6. The method of claim 1 wherein the patient's CKD is caused by T2DM.

7. The method of claim 1 wherein the patient has eGFR between 15-59 mL/min/1.73 m.sup.2 and UACR greater than 300 mg/g.

8. The method of claim 1 wherein the patient has eGFR between 15-29 mL/min/1.73 m.sup.2.

9. (canceled)

10. (canceled)

11. (canceled)

12. The method of claim 1 wherein the patient has eGFR between 15-44 mL/min/1.73 m.sup.2.

13. (canceled)

14. (canceled)

15. The method of claim 1 wherein the patient has UACR 300 mg/g.

16. The method of claim 1, wherein said administration is continued for at least 1 year.

17. (canceled)

18. The method of claim 1, wherein the effective amount of dulaglutide is 1.5 mg.

19. The method of claim 1, wherein said attenuation in progression of the patient's CKD is reflected in an increase in time to one or more of: a 40% decrease in eGFR; progression to ESRD; renal death; and/or cardiovascular death.

20. (canceled)

21. The method of claim 1, further comprising administering an ACE inhibitor and/or an ARB.

22.-41. (canceled)

Description

EXAMPLES

[0121] In a phase 3 clinical study, once weekly dulaglutide in doses of 0.75 mg or 1.5 mg is compared to daily titrated insulin glargine, each combined with insulin lispro provided for postprandial glucose control, in patients with moderate and severe CKD and T2DM. The study is designed as a multicenter, parallel-arm, randomized, 52-week treatment study assessing the efficacy and safety of dulaglutide compared to insulin glargine. The primary objective is to determine whether dulaglutide is noninferior to insulin glargine with respect to HbA1c in this patient population at 26 weeks, but secondary objectives were also designed to determine effects on eGFR and albuminuria.

[0122] Participants are randomized (1:1:1) to once weekly dulaglutide 1.5 mg (N=192), once weekly dulaglutide 0.75 mg (N=190) or titrated insulin glargine (N=194). Stratification factors included time of enrollment, macroalbuminuria, geographic region, and CKD stage.

[0123] Baseline characteristics are similar between treatment groups, including for CKD related characteristics, as indicated in Table 2 below:

TABLE-US-00003 TABLE 2 Baseline Insulin Characteristics DU 1.5 mg DU 0.75 mg Glargine (mITT population) N = 183 N = 180 N = 186 Duration of 17.7 8.8 18.0 8.9 18.6 8.8 diabetes, years Duration of CKD 4.2 5.7 4.1 5.0 3.5 4.0 stage 3 or higher, years HbA1c, % 8.6 0.9 8.6 1.1 8.6 1.0 eGFR (CKD-EPI 38.0 13.3 38.4 12.3 38.5 13.0 creatinine equation), ml/min/1.73 m.sup.2 60 Baseline 8 (4.4) 6 (3.3) 13 (7.0) eGFR < 90 45 Baseline 51 (27.9) 51 (28.3) 50 (26.9) eGFR < 60 30 Baseline 70 (38.3) 72 (40.0) 64 (34.4) eGFR < 45 15 Baseline 52 (28.4) 51 (28.3) 58 (31.2) eGFR < 30 Baseline eGFR <15 2 (1.1) 0 (0.0) 1 (0.5) UACR, mg/g 756.5 1294.7 839.0 1383.6 891.6 1501.3 30 UACR 300 73 (39.9) 56 (31.3) 55 (29.6) (mg/g) UACR > 300 80 (43.7) 81 (45.3) 84 (45.2) (mg/g) Data presented as mean SD or n (%), Abbreviations: DU = dulaglutide; mITT = modified intent-to-treat population, which includes all randomized patients who receive at least 1 dose of randomized treatment (dulaglutide or insulin glargine) and who have at least 1 post-randomization HbA1c value, classified according to their assigned treatment.

[0124] 26 week A1c data are provided in Table 3 below:

TABLE-US-00004 TABLE 3 Primary Endpoint Insulin (26 week, mITT DU 1.5 mg DU 0.75 mg Glargine population) (N = 183) (N = 180) (N = 186) HbA1c change (%) 1.19 (0.13)* 1.12 (0.12)* 1.13 (0.13)* Percentage of pt 37.5 31.7 34.6 with A1c <7% Percentage of pt 78.3 72.6 75.3 with A1c <8% Data are reported as LSM (SE) unless otherwise indicated. , multiplicity adjusted 1-sided p < 0.001 for noninferiority versus insulin glargine with a 0.4% margin or 0.3% margin, respectively, and *2-sided p < 0.001 change from baseline. Table Excluding Data after Rescue or Study Drug Discontinuation. Abbreviations: LSM = least squares mean; SE = standard error; pt = participant(s).

[0125] The data support that dulaglutide produced comparable glycemic control as compared to insulin glargine.

[0126] 26-week data on eGFR and albuminuria in the overall study participants and by UACR300 mg/g and UACR300 mg/g are provided in Table 4 below.

TABLE-US-00005 TABLE 4 26-week data on eGFR are presented as change from baseline LSM (95% CI), and data on UACR are presented as percent change from baseline LSM (95% CI) as obtained via log-transformed analysis; safety population, which includes all patients (regardless of missing post- randomization HbA1c data), classified according to the treatment actually received. All Participants Participants with UACR > Participants with UACR eGFR, 300 mg/g (n = 258) 300 mg/g (n = 317) Treatment mL/min/1.73 m.sup.2 % UACR eGFR, eGFR, arm (n = 576) (n = 575) mL/min/1.73 m.sup.2 % UACR mL/min/1.73 m.sup.2 % UACR DU 1.5 mg 0.1# 27.7** 1.9*# 43.1**# 0.3 0.4 (1.2, 1.0) (38.7, 14.8) (3.5, 0.4) (54.7, 28.6) (1.0, 1.7) (19.2, 22.8) DU 0.75 mg 0.4# 26.7** 2.6**# 25.3* 0.3 18.0 (1.4, 0.7) (37.9, 13.5) (4.2, 1.1) (40.2, 6.8) (1.0, 1.7) (33.6, 1.3) Glargine 1.9** 16.4* 4.8** 14.3 0.7 5.7 (3.0, 0.9) (29.0, 1.5) (6.3, 3.4) (30.9, 6.3) (2.0, 0.7) (23.2, 15.8) *2-sided p < 0.05 and **2-sided p < 0.001 change from baseline, #2-sided p < 0.05 versus insulin glargine. Abbreviations: CI = confidence interval.

[0127] After 26 weeks eGFR for the all participants group, and participants with UACR >300 mg/g group, decreased significantly with insulin glargine, indicating an expected progression of CKD. eGFR surprisingly remained stable with dulaglutide in the all participants group, and decreased significantly less than observed for insulin glargine in the UACR >300 mg/g group. Participants in the UACR >300 mg/g group receiving dulaglutide 1.5 mg also had greater reductions in UACR compared to insulin glargine.

[0128] 52 week A1c data are provided in Table 5 below:

TABLE-US-00006 TABLE 5 Primary Endpoint Insulin (52 week, mITT DU 1.5 mg DU 0.75 mg Glargine population) (N = 183) (N = 180) (N = 186) A1c change, % 1.10 (0.13)* 1.10 (0.12)* 1.00 (0.12)* Percentage of pt 32.9 33.5 29.1 with A1c <7% Percentage of pt 69.1 69.5 70.3 with A1c <8% Data are reported as LSM (SE) unless otherwise indicated. , multiplicity adjusted 1-sided p < 0.001 for noninferiority versus insulin glargine with a 0.4% margin or 0.3% margin, respectively, and *2-sided p < 0.001 change from baseline. Excluding Data after Rescue or Study Drug Discontinuation.

[0129] 52-week data on eGFR and albuminuria in the overall study participants and by UACR300 mg/g and UACR 300 mg/g are provided in Table 6 below.

TABLE-US-00007 TABLE 6 52-week data on eGFR are presented as change from baseline LSM (95% CI), and data on UACR are presented as percent change from baseline LSM (95% CI) as obtained via log-transformed analysis; safety population, which includes all patients (regardless of missing post- randomization A1c data), classified according to the treatment actually received. Participants with UACR > Participants with UACR All Participants (N = 576) 300 mg/g (n = 258) 300 mg/g (n = 317) Treatment eGFR, eGFR, eGFR, arm mL/min/1.73 m.sup.2 % UACR mL/min/1.73 m.sup.2 % UACR mL/min/1.73 m.sup.2 % UACR DU 1.5 mg 1.1 22.5* 3.4**# 29.0*# 1.4 3.4 (2.4, 0.2) (35.1, 7.5) (5.4, 1.4) (43.0, 11.5) (2.0, 1.3) (24.0, 22.8) DU 0.75 mg 1.5* 20.1* 5.2** 12.3 0.2 15.3 (2.8, 0.2) (33.1, 4.6) (7.1, 3.2) (29.0, 8.5) (1.4, 1.9) (33.6, 8.0) Insulin 2.9** 13.0 6.3** 0.1 1.3 9.9 Glargine (4.2, 1.6) (27.1, 3.9) (8.2, 4.4) (18.8, 23.4) (2.9, 0.4) (29.0, 14.4) *2-sided p < 0.05 and **2-sided p < 0.001 change from baseline, #2-sided p < 0.05 versus insulin glargine.

[0130] The 52-week data in Tables 5 and 6 show that dulaglutide continues to provide comparable glycemic control to insulin glargine out to 52 weeks, but that the attenuated rate of eGFR decline and reductions in UACR observed compared to insulin glargine after 26 weeks are maintained, particularly for participants with UACR >300 mg/g receiving 1.5 mg dulaglutide.