FLUTICASONE FUROATE IN THE TREATMENT OF COPD

Abstract

The present invention relates to a method of reducing the rate of decline in lung function in a human patient with COPD, wherein the human patient having COPD has a blood eosinophil count of ≥150 cells/μL, and further wherein the method comprises administering to the patient an inhaled pharmaceutical product comprising fluticasone furoate.

Claims

1-18. (canceled)

19. A method of reducing the rate of decline in lung function in a human patient with COPD, wherein the patient having COPD has a blood eosinophil count of ≥150 cells/μL, and further wherein the method comprises administering to the patient an inhaled pharmaceutical product comprising fluticasone furoate.

20. The method of claim 19, wherein the inhaled pharmaceutical product comprises a dry powder inhaler, said dry powder inhaler comprising one or more dry powder compositions.

21. The method of claim 20, wherein said one or more dry powder-compositions are in unit-dose form.

22. The method of claim 21, wherein fluticasone furoate is present in an amount of about 100 mcg/dose.

23. The method of claim 22, wherein the inhaled pharmaceutical product further comprises lactose monohydrate.

24. The method of claim 19, wherein the inhaled pharmaceutical product further comprises umeclidinium bromide.

25. The method of claim 24, wherein the inhaled pharmaceutical product-comprises a dry powder inhaler, wherein said dry powder inhaler comprises one or more dry powder compositions.

26. The method of claim 25, wherein said one or more dry powder compositions are present in unit-dose form.

27. The method of claim 26, wherein said fluticasone furoate is present in an amount of about 100 mcg/dose, and said umeclidinium bromide is present in an amount of about 62.5 mcg (of the free cation)/dose or 125 mcg (of the free cation)/dose.

28. The method of claim 26, wherein said one or more dry powder compositions comprises a first and a second dry powder composition, each in unit dose form, wherein said first dry powder composition comprises said fluticasone furoate in an amount of about 100 mcg/dose; and; said second dry powder composition comprises said umeclidinium bromide in an amount of about 62.5 mcg (of the free cation)/dose or 125 mcg (of the free cation)/dose.

29. The method of claim 28, wherein said first dry powder composition comprises said fluticasone furoate and lactose monohydrate; and said second dry powder composition comprises said umeclidinium bromide and further comprises lactose monohydrate, and magnesium stearate.

30. The method of claim 29, wherein said magnesium stearate is present in an amount of 0.6% w/w of said second composition.

31. The method of claim 29, wherein said first and second compositions in unit dose form are presented for simultaneous administration.

32. The method of claim 19, wherein the inhaled pharmaceutical product further comprises vilanterol trifenatate.

33. The method of claim 32, wherein the inhaled pharmaceutical product comprises a dry powder inhaler, said dry powder inhaler comprising one or more dry powder compositions.

34. The method of claim 33, wherein said one or more dry powder compositions are present in unit-dose form.

35. The method of claim 34, wherein said fluticasone furoate is present in an amount of about 100 mcg/dose and said vilanterol trifenatate is present in an amount of about 25 mcg (of the free base)/dose.

36. The method of claim 35, wherein said dry powder inhaler comprises a first and a second dry powder composition, said first dry powder composition comprising said fluticasone furoate in an amount of about 100 mcg/dose, and; said second dry powder composition comprising said vilanterol trifenatate in an amount of about 25 mcg (of the free base)/dose.

37. The method of claim 36, wherein said first dry powder composition further comprises lactose monohydrate; and said second dry powder composition further comprises lactose monohydrate and magnesium stearate.

38. The method of claim 36, wherein said magnesium stearate is present in an amount of 0.6% w/w of the second composition.

39. The method of claim 36, wherein said first and second dry powder compositions are in unit dose form and are presented for simultaneous administration.

40. The method of claim 19, wherein the inhaled pharmaceutical product further comprises umeclidinium bromide and vilanterol trifenatate.

41. The method of claim 40, wherein the inhaled pharmaceutical product comprises a dry powder inhaler, wherein said dry powder inhaler comprising one or more dry powder compositions.

42. The method of claim 41, wherein said one or more dry powder compositions are in unit-dose form.

43. The method of claim 42, wherein said fluticasone furoate is present in an amount of about 100 mcg/dose, said umeclidinium bromide is in an amount of about 62.5 mcg (of the free cation)/dose or 125 mcg (of the free cation)/dose, and said vilanterol trifenatate is in an amount of about 25 mcg (of the free base)/dose.

44. The method of claim 43, wherein the dry powder inhaler comprises a first and a second dry powder composition, said first dry powder composition comprising said fluticasone furoate in an amount of about 100 mcg/dose, and; said second dry powder composition comprising said umeclidinium bromide in an amount of about 62.5 mcg (of the free cation)/dose or 125 mcg (of the free cation)/dose and said vilanterol trifenatate in an amount of about 25 mcg (of the free base)/dose.

45. The method of claim 44, wherein said first dry powder composition further comprises lactose monohydrate; and said second dry powder composition further comprises lactose monohydrate and magnesium stearate.

46. The method of claim 45, wherein said magnesium stearate is present in an amount of 0.6% w/w of the second composition.

47. The method of claim 45, wherein said first and second dry powder compositions are in unit dose form and are presented for simultaneous administration.

Description

EXAMPLE 1

Re-Analysis of Clinical Study Data

[0147] Methods: The results of ISOLDE (Burge P S et al BMJ 2000; 320: 1297-303), a 3-year study of the effects of fluticasone propionate (FP) 500 mcg twice daily on rate of decline of FEV.sub.1 in well-characterised COPD patients were re-analysed by baseline blood eosinophil count (≥2%, <2%).
Results: The pre-specified analysis of ISOLDE showed no effect of FP on the rate of decline of FEV.sub.1 for FP vs. placebo. Eosinophil count was <2% in 68% of patients; the spirometric characteristics of these patients were similar to those with an eosinophil count ≥2%. Patients with an eosinophil count <2% showed no difference in rate of decline of FEV.sub.1 with FP vs. placebo (figure). In patients with an eosinophil count ≥2%, FP 500 mcg slowed the rate of decline of lung function by 38 mL per year compared with placebo (p=0.001).
Conclusion: A baseline blood eosinophil count of 2% identifies a group of COPD patients who show a slower rate of decline of FEV.sub.1 when treated with inhaled corticosteroids.

EXAMPLE 2

Clinical Study

[0148] A 52-week, randomised, double-blind, 3-arm parallel group clinical study is performed to compare the efficacy, safety and tolerability of the fixed dose triple combination FF/UMEC/VI with the fixed dose dual combinations of FF/VI and UMEC/VI, all given once daily in the morning via a dry powder inhaler in subjects with COPD.

[0149] The treatment groups:

[0150] FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg

[0151] FF/VI 100 mcg/25 mcg

[0152] UMEC/VI 62.5 mcg/25 mcg

The primary objective is to evaluate the efficacy of FF/UMEC/VI to reduce the annual rate of moderate and severe exacerbations compared with dual therapy of FF/VI or UMEC/VI in subjects with COPD. A secondary objective is to evaluate the efficacy of FF/UMEC/VI to reduce exacerbations compared with UMEC/VI in the subset of subjects with a blood eosinophil count ≥150 cells/μl. An extension of the above study is performed with the primary objective of assessing the rate of decline in FEV.sub.1 for FF/UMEC/VI versus UMEC/VI in the high eosinophil group (≥150 cells/μl).

EXAMPLE 3

Post-Hoc Analysis of Clinical Study Data

[0153] Fluticasone furoate (FF)/vilanterol (VI) reduces COPD exacerbations when compared with treatment with VI alone. Identification of a simple biomarker would allow targeted treatment. The objective of this post-hoc analysis of clinical study data was to compare exacerbation rates between FF/VI and VI in patients with moderate to very severe COPD, stratified by blood eosinophil level.
Methods: We evaluated the use of blood eosinophil count through post-hoc analysis of pooled data from two randomised, double-blind, placebo-controlled 1-year trials (Dransfield M T et al, Lancet Resp Med 2013; 1: 210-23) comparing FF/VI (50/25 mcg, 100/25 mcg or 200/25 mcg once daily) to VI (25 mcg once daily) in patients with COPD and a history of exacerbations in the last year. We evaluated the FF-related reduction in exacerbation rates in patients with eosinophil counts <2% and ≥2%.
Results: 3177 patients provided blood samples at study entry; 2083 (66%) had eosinophils ≥2%. Exacerbation rates were higher in the subgroup treated with VI alone (1.28 vs 0.91/patient/yr). Baseline eosinophil count was significantly associated with reduced exacerbation rates with the three doses of FF/VI combined. Exacerbations were reduced by 29% (p<0.001) in patients with eosinophils ≥2% and 10% (p=0.283) in those with <2%. Treatment differential increased with increasing FF dose. In patients with eosinophils ≥2% receiving FF/VI 50/25 mcg, 100/25 mcg and 200/25 mcg, exacerbations reductions were, respectively: 21%, 33%, 33% (all p<0.01). For eosinophils <2%, the corresponding reductions were 9%, 18%, 3%.
Conclusion: Blood eosinophil level is a promising biomarker of response for inhaled corticosteroid (ICS) treatment in patients with COPD.