Claims for Patent: RE49444

Summary for Patent: RE49444

Title:	Method of treating osteoporosis comprising administration of PTHrP analog
Abstract:	The present invention provides a storage-stable composition containing a parathyroid hormone-related protein (PTHrP) and methods of using a PTHrP and the PTHrP compositions described herein to treat osteoporosis, to increase bone mass or to increase bone quality. The composition is storage stable, in sterile form, and in general may be stored at room temperature for at least several weeks to allow convenient parenteral administration to human patients.
Inventor(s):	Michael J. Dey, Nathalie Mondoly, Benedicte Rigaud, Bart Henderson, C. Richard Lyttle, Zhengxin Dong
Assignee:	Ipsen Pharma SAS, Radius Health Inc
Application Number:	US17/133,968
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent RE49444
Patent Claims:	1. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 to a human in need thereof. 2. The method of claim 1, wherein the composition further comprises an effective amount of buffer to maintain the pH between 2 and 7. 3. The method of claim 1, wherein the buffer is selected from the group consisting of acetate, tartrate, phosphate and citrate buffers. 4. The method of claim 3, wherein the buffer is an acetate buffer. 5. The method of claim 4, wherein the buffer is acetic acid and sodium acetate. 6. The method of claim 2, wherein the pH is maintained between 3 and 6. 7. The method of claim 6, wherein the pH is maintained between 4 and 6. 8. The method of claim 7, wherein the pH is maintained between 4.5 and 5.6. 9. The method of claim 1, wherein the human is a post-menopausal woman. 10. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma Cmax of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 from between 255.57 pg/mL and 364.3 pg/mL or from between 367.2 pg/mL and 504.8 pg/mL in said subject. 11. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma Tmax of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 from between 0.251 hours and 1.01 hours, or from between 0.500 hours and 1.00 hours in said subject. 12. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma t1/2 of [Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34)NH2 from between 1.585 hours and 3.015 hours, or from between 1.265 hours and 2.115 hours in said subject. 13. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma Cmax of [Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34)NH2 from between 255.57 pg/mL and 364.3 pg/mL and a Tmax from between 0.251 hours and 1.01 hours, or a Cmax from between 367.2 pg/mL and 504.8 pg/mL and a Tmax from between 0.500 hours and 1.00 hours in said subject. 14. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma Cmax of [Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34)NH2 from between 255.57 pg/mL and 364.3 pg/mL and a Tmax from between 0.251 hours and 1.01 hours and a t1/2 of between 1.585 hours and 3.015 hours, or a Cmax from between 367.2 pg/mL and 504.8 pg/mL and a Tmax from between 0.500 hours and 1.00 hours and a t1/2 of between 1.265 hours and 2.115 hours in said subject. 15. The method according to claim 2, wherein the pH is maintained at about 5.1. 16. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 to a human in need thereof, wherein the composition is delivered in a multi-dose injection pen. 17. The method according to claim 16, wherein the composition further comprises an anti-microbial agent. 18. The method according to claim 17, wherein the anti-microbial agent is selected from phenol, chlorocresol, and methylparaben/propylparaben, or a combination thereof. 19. The method according to claim 18, wherein the anti-microbial agent is phenol. 20. The method according to claim 19, wherein the composition comprises 5 mg/mL phenol. 21. The method according to claim 16 or claim 17, wherein the composition further comprises a buffer. 22. The method according to claim 21, wherein the composition comprises a buffer in an amount effective to maintain the pH at about 5.1. 23. The method according to claim 22, wherein the pH is maintained at about 5.1. 24. The method according to claim 21, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof. 25. The method according to claim 22, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof. 26. The method according to claim 23, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof. 27. The method according to claim 24, wherein the buffer is an acetate buffer. 28. The method according to claim 25, wherein the buffer is an acetate buffer. 29. The method according to claim 26, wherein the buffer is an acetate buffer. 30. The method according to claim 27, wherein the acetate buffer comprises acetic acid and sodium acetate. 31. The method according to claim 28, wherein the acetate buffer comprises acetic acid and sodium acetate. 32. The method according to claim 29, wherein the acetate buffer comprises acetic acid and sodium acetate. 33. The method according to claim 30, wherein the sodium acetate is sodium acetate trihydrate. 34. The method according to claim 31, wherein the sodium acetate is sodium acetate trihydrate. 35. The method according to claim 32, wherein the sodium acetate is sodium acetate trihydrate. 36. The method according to claim 17, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL six hours following bacterial exposure. 37. The method according to claim 36, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL 24 hours following bacterial exposure. 38. The method according to claim 36, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL 28 days following bacterial exposure. 39. The method according to claim 36, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure. 40. The method according to claim 37, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure. 41. The method according to claim 38, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure. 42. The method according to claim 36, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure. 43. The method according to claim 37, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure. 44. The method according to claim 38, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure. 45. The method according to claim 17, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 7 days following exposure to the yeast or mold. 46. The method according to claim 45, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 7 days following exposure to the yeast or mold. 47. The method according to claim 45, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 28 days following exposure to the yeast or mold. 48. The method according to claim 45, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold. 49. The method according to claim 46, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold. 50. The method according to claim 47, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold. 51. The method according to claim 45, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold. 52. The method according to claim 46, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold. 53. The method according to claim 47, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold. 54. The method according to claim 16, wherein the concentration of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 in the composition is at least 98.9% of its initial concentration at t=0 after 1 month. 55. The method according to claim 16, wherein the concentration of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 in the composition is at least 96.3% of its initial concentration at t=0 after 3 months. 56. The method according to claim 16, wherein the concentration of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 in the composition is at least 99.5% of its initial concentration at t=0 after 4.5 months. 57. The method according to claim 54, wherein the concentration of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 in the composition is at least 98.9% of its initial concentration at t=0 after 1 month at 25° C. 58. The method according to claim 55, wherein the concentration of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 in the composition is at least 96.3% of its initial concentration at t=0 after 3 months at 25° C. 59. The method according to claim 56, wherein the concentration of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 in the composition is at least 99.5% of its initial concentration at t=0 after 4.5 months at 5° C. 60. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 to a human in need thereof, wherein the composition is prepared according to a process comprising: (a) dissolving [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2, an anti-microbial agent, and a buffer in water to form a solution; and (b) filtering the solution through a 0.2 micron filter. 61. The method according to claim 60, wherein the anti-microbial agent is selected from phenol, chlorocresol, and methylparaben/propylparaben, or a combination thereof. 62. The method according to claim 61, wherein the anti-microbial agent is phenol. 63. The method according to claim 62, wherein the composition comprises 5 mg/mL phenol. 64. The method according to claim 60, wherein the composition comprises a buffer in an amount effective to maintain the pH at about 5.1. 65. The method according to claim 64, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof. 66. The method according to claim 65, wherein the buffer is an acetate buffer. 67. The method according to claim 66, wherein the acetate buffer comprises acetic acid and sodium acetate. 68. The method according to claim 67, wherein the sodium acetate is sodium acetate trihydrate. 69. A method of treating osteoporosis, the method comprising daily subcutaneous administration to a human in need thereof a composition comprising 80 μg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2, wherein the composition is formulated to achieve one or more of the following pharmacokinetic parameters: Pharmacokinetic Parameters Mean ± SD Cmax (pg/mL) 310 ± 54.3 Tmax (hr)# 0752 (0.251, 1.01) Tlast (hr)# 7.00 (4.00.12.01 AUC0-t (pg * hr/mL) 949.89 ± 493.58 AUC0-inf (pg * hr/mL) 1055.6 ± 513.61 AUC0-tau (pg * hr/mL) 1053.2 ± 511.27 t1/2 (hr) 2.30 ± 0715 Kel (1/hr) 0.335 ± 0.127 AUCR 0.892 ± 0.0369 CL/F (L/hr) 94.61 ± 51.09 ln (Cmax) 5.722 ± 0.1732 ln (AUC0-t) 6.740 ± 0.5206 ln (AUC0-inf) 6.855 ± 0.5063 ln (AUC0-tau) 6.853 ± 0.5050 #= Tmax and Tlast are presented as Median (minimum, Maximum). 70. The method according to claim 69, wherein the dosing regimen has been determined to achieve a Cmax plasma levels of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 between 255.7 pg/mL and 364.3 pg/mL. 71. The method according to claim 69, wherein the dosing regimen has been determined to achieve a plasma Tmax for [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 between 0.251 hours and 1.01 hours. 72. The method according to claim 69, wherein the dosing regimen has been determined to achieve a plasma t1/2 of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 between 1.585 hours and 3.015 hours. 73. The method according to claim 69, wherein the dosing regimen has been determined to achieve a net plasma AUC(0-inf) of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 between 541.99 pg h/mL and 1569.21 pg h/mL. 74. A method of treating osteoporosis, the method comprising daily subcutaneous administration to a human in need thereof a composition comprising 80 μg of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2, wherein the composition is formulated to achieve one or more of the following pharmacokinetic parameters: Pharmacokinetic Parameters Mean ± SD Cmax (pg/mL) 436 ± 68.8 Tmax (hr)# 0.507 (0.500, 1.00) Tlast (hr)# 6.00 (4.00, 8.02) AUC0-t (pg * hr/mL) 1003.0 ± 383.45 AUC0-tau (pg * hr/mL) 1080.3 ± 408.57 t1/2 (hr) 1.69 ± 0.425 Kel (1/hr) 0.437 ± 0.124 CL/F (L/hr) 82.74 ± 26.95 AI 1.12 ± 0.353 ln (Cmax) 6.065 ± 0.1628 ln (AUC0-t) 6.851 ± 0.3623 ln (AUC0-tau) 6.927 ± 0.3581 #= Tmax and Tlast are presented as Median (minimum, Maximum). 75. The method according to claim 74, wherein the dosing regimen has been determined to achieve a Cmax plasma levels of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 between 367.2 pg/mL and 504.8 pg/mL. 76. The method according to claim 74, wherein the dosing regimen has been determined to achieve a plasma Tmax for [Glu22,25, Leu23,28,31, Aib29, L26,30]hPTHrP(1-34)NH2 between 0.500 hours and 1.00 hours. 77. The method according to claim 74, wherein the dosing regimen has been determined to achieve a plasma t1/2 of [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 between 1.265 hours and 2.115 hours. 78. The method according to claim 69, wherein the composition is delivered in a multi-dose injection pen. 79. The method according to claim 74, wherein the composition is delivered in a multi-dose injection pen.