Methods for Treating Idiopathic Pulmonary Fibrosis with Dupirfenidone - Patent application
Deuterium-enriched pirfenidone (LYT-100) addresses tolerability issues in IPF treatment by increasing doses and dividing them, improving compliance and efficacy through reduced adverse events and slower disease progression.
Patent Information
- Application Number
- JP2024540710
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2022-12-13
- Filing Date
- 2023-01-05
- Publication Date
- 2025-01-24
AI Technical Summary
Current treatments for idiopathic pulmonary fibrosis (IPF) like pirfenidone face significant tolerability issues, leading to dose reductions, discontinuations, and reduced clinical efficacy due to side effects such as gastrointestinal intolerance, headaches, and photosensitivity, limiting their effectiveness and patient compliance.
Administration of deuterium-enriched pirfenidone (LYT-100) at higher doses divided into multiple smaller doses to enhance tolerability and maintain therapeutic efficacy, with total daily doses ranging from 825 mg to 2475 mg, achieving 1.1 to 1.9 times the full-body exposure of regular pirfenidone.
Enhances tolerability by reducing adverse events, improves patient compliance, and maintains clinical efficacy by slowing IPF progression, as demonstrated by reduced decline in lung function and fewer treatment interruptions.
Smart Images
Figure 2025502023000001_ABST
Abstract
Claims
1. A method of treating idiopathic pulmonary fibrosis (IPF), comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 1】 at a total daily dose of about 825 mg to about 2500 mg, wherein the IPF is treated in the subject.
2. 10. The method of claim 1, wherein the administration is three times daily.
3. 3. The method of claim 1 or claim 2, wherein the total daily dose is 825 mg of LYT-100 administered in three equal doses of 275 mg each.
4. 3. The method of claim 1 or claim 2, comprising administering LYT-100 at a first total daily dose of 825 mg for a first period of time, at a second total daily dose of 1650 mg for a second period of time, and at a total daily maintenance dose of 2475 mg thereafter.
5. 3. The method of claim 1 or claim 2, comprising administering LYT-100 at a first total daily dose of 825 mg for a first period of 7 days, at a second total daily dose of 1650 mg for a second period of 7 days, and at a total daily maintenance dose of 2475 mg thereafter.
6. A method of treating idiopathic pulmonary fibrosis (IPF), comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 2】 at a total daily dose of about 1650 mg to about 2500 mg, wherein the IPF is treated in the subject.
7. 7. The method of claim 6, wherein the administration is three times daily.
8. 8. The method of claim 6 or claim 7, wherein the total daily dose is administered in three equal doses of 550 mg each.
9. 8. The method of claim 6 or claim 7, wherein the total daily dose is administered in three equal doses of 825 mg each.
10. A method of treating idiopathic pulmonary fibrosis (IPF), comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 3】 in a total daily dose of 1650 mg, and administering the LYT-100 in three equal doses of 550 mg each to treat IPF in the subject.
11. A method of treating idiopathic pulmonary fibrosis (IPF), comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 4】 at a total daily dose of 2475 mg, and administering the LYT-100 in three equal doses of 825 mg each, to treat IPF in the subject.
12. The method of any one of claims 1 to 11, wherein the LYT-100 is administered without regard to food.
13. The method of any one of claims 1 to 11, wherein the LYT-100 is administered without food.
14. The method of any one of claims 1 to 11, wherein the LYT-100 is administered with food.
15. The method of any one of claims 1 to 14, wherein said treating prevents, delays, or slows the progression of respiratory dysfunction in said subject.
16. 16. The method of claim 15, wherein respiratory function is determined by measuring the subject's forced vital capacity (FVC).
17. 17. The method of claim 16, wherein the progression of respiratory dysfunction in the subject is determined by measuring changes in FVC over the treatment period.
18. 18. The method of claim 17, wherein the treatment period for measuring changes in FVC is at least 26 weeks.
19. 18. The method of claim 17, wherein the treatment period for measuring changes in FVC is at least 52 weeks.
20. 18. The method of claim 17, wherein the treatment period for measuring changes in FVC is from baseline to a treatment period selected from at least 26 weeks, at least 52 weeks, at least 78 weeks, or at least 104 weeks.
21. 18. The method of claim 17, wherein the change in FVC is measured from baseline to at least 26 weeks of treatment.
22. 18. The method of claim 17, wherein the change in FVC is measured from baseline to at least 52 weeks of treatment.
23. 18. The method of claim 17, wherein the change in FVC is measured as a decrease in FVC.
24. 24. The method of claim 23, wherein the decline in FVC is less than in a subject who has not received LYT-100.
25. 24. The method of claim 23, wherein the decline in FVC (mL) over a treatment period of at least 26 weeks is less than the percentage decline exhibited by a subject who has not received LYT-100.
26. 24. The method of claim 23, wherein the decline in FVC (mL) over a treatment period of at least 52 weeks is less than the rate of decline exhibited by a subject who has not received LYT-100.
27. 27. The method of any one of claims 17 to 26, wherein the change in FVC is measured as a decrease in FVC % predicted (FVCpp).
28. 28. The method of claim 27, wherein the decrease in FVCpp is less than in a subject who has not received LYT-100.
29. 28. The method of claim 27, wherein the decline in FVCpp over a treatment period of at least 26 weeks is less than the percentage decline exhibited by a subject who has not received LYT-100.
30. 30. The method of any one of claims 27-29, wherein the subject exhibits a decrease in FVCpp of less than 5% or more than 5% from baseline to week 26 of treatment.
31. 31. The method of any one of claims 27 to 30, wherein the decline in FVCpp over a treatment period of at least 52 weeks is less than the percentage decline exhibited by a subject who has not received LYT-100.
32. The method of any one of claims 27-31, wherein the subject exhibits a decline in FVCpp from baseline to week 52 of treatment of less than 10% or more than 10%.
33. 33. The method of any one of claims 1-32, wherein said treatment slows the progression of said IPF in said subject compared to a subject who has not received LYT-100.
34. 34. The method of claim 33, wherein the time to progression of IPF is longer in the treated subject compared to a subject who has not received LYT-100.
35. 35. The method of claim 33 or claim 34, wherein the progression of IPF is determined by measuring the decline in FVC (mL), or FVCpp, or both.
36. The method of any one of claims 33 to 35, wherein the progression of IPF is measured over a treatment period of at least 26 weeks.
37. 37. The method of claim 36, wherein progression of IPF is determined by a decline of 5% or more in FVCpp.
38. 36. The method of any one of claims 33 to 35, wherein the progression of IPF is measured over a treatment period of at least 52 weeks.
39. 39. The method of claim 38, wherein progression of IPF is determined by a decline of 10% or more in FVCpp.
40. 40. The method of any one of claims 1 to 39, wherein the subject exhibits a prolonged time to hospitalization due to respiratory dysfunction compared to a subject who has not received LYT-100.
41. 41. The method of claim 40, wherein the hospitalization is a first hospitalization.
42. 41. The method of claim 40, wherein the hospitalization is not a first hospitalization.
43. 43. The method of any one of claims 40 to 42, wherein the time to hospitalization due to respiratory dysfunction is measured over a treatment period of at least 26 weeks.
44. 43. The method of any one of claims 40 to 42, wherein the time to hospitalization due to respiratory dysfunction is measured over a treatment period of at least 52 weeks.
45. 45. The method of any one of claims 1 to 44, wherein the subject has fewer hospitalizations due to respiratory dysfunction compared to a subject who has not received LYT-100.
46. 46. The method of claim 45, wherein the number of hospitalizations due to respiratory dysfunction is measured over a treatment period of at least 26 weeks.
47. 46. The method of claim 45, wherein the number of hospitalizations due to respiratory dysfunction is measured over a treatment period of at least 52 weeks.
48. 48. The method of any one of claims 1 to 47, wherein the subject has a shorter length of hospitalization(s) for respiratory dysfunction compared to a subject who has not received LYT-100.
49. 49. The method of claim 48, wherein the length of hospital stay(s) due to respiratory dysfunction is measured over a treatment period of at least 26 weeks.
50. 49. The method of claim 48, wherein the length of hospitalization for the respiratory dysfunction(s) is measured over a treatment period of at least 52 weeks.
51. The method of any one of claims 1 to 50, wherein the subject has an alteration in one or more serum biomarkers associated with respiratory dysfunction compared to a subject who has not received LYT-100.
52. 52. The method of claim 51, wherein the serum biomarker is collagen type 4.
53. 53. The method of claim 51 or claim 52, wherein the change in serum biomarker(s) associated with respiratory dysfunction is measured over a treatment period of at least 26 weeks.
54. 46. The method of claim 44 or claim 45, wherein the change in serum biomarker(s) associated with respiratory dysfunction is measured over a treatment period of at least 52 weeks.
55. 55. The method of any one of claims 1 to 54, wherein the subject exhibits a prolonged time to death from respiratory dysfunction compared to a subject not receiving LYT-100.
56. 56. The method of claim 55, wherein the time to death from respiratory dysfunction is measured over a treatment period of at least 26 weeks.
57. 56. The method of claim 55, wherein the time to death from respiratory dysfunction is measured over a treatment period of at least 52 weeks.
58. 58. The method of any one of claims 1-57, wherein the subject exhibits improvement in treatment as determined in one or more of the following: King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score; St. George's Respiratory Questionnaire (SGRQ-I) domain scores; EuroQol 5 Item (EQ5D) questionnaire score; and cough visual analog scale (VAS) compared to a subject who has not received LYT-100.
59. 59. The method of claim 58, wherein the improvement in treatment is measured over a treatment period of at least 26 weeks.
60. 60. The method of claim 58, wherein the improvement in treatment is measured over a treatment period of at least 52 weeks.
61. 61. The method of any one of claims 1-60, wherein the subject is treated without dose reduction of the administered daily dose throughout the treatment period.
62. 62. The method of any one of claims 1 to 61, wherein the subject is treated without interruption or temporary cessation of treatment throughout the treatment period.
63. 63. The method of any one of claims 1 to 62, wherein the subject is treated without discontinuation of treatment throughout the treatment period.
64. 64. The method of any one of claims 61 to 63, wherein the treatment period is at least 26 weeks.
65. 65. The method of any one of claims 61 to 64, wherein the treatment period is at least 52 weeks.
66. 66. The method of any one of claims 1-65, wherein the subject exhibits a reduced incidence of one or more adverse events (AEs) compared to subjects treated with 801 mg TID pirfenidone over the same treatment period.
67. 67. The method of any one of claims 1-66, wherein the subject exhibits a shortened duration of one or more adverse event(s) (AEs) compared to subjects treated with 801 mg TID pirfenidone for the same treatment period.
68. 68. The method of claim 66 or claim 67, wherein the one or more adverse events are gastrointestinal related adverse events selected from nausea, vomiting, abdominal pain or bloating, dyspepsia, diarrhea, decreased appetite, and constipation.
69. 69. The method of any one of claims 66-68, wherein the one or more adverse events comprises a nervous system related adverse event selected from headache, dizziness, and somnolence.
70. 70. The method of any one of claims 66-69, wherein the one or more adverse events comprise fatigue, drug intolerance, or both.
71. 71. The method of any one of claims 66 to 70, wherein the one or more adverse events comprise elevation of AST, ALT, GGT, and / or liver toxicity.
72. 72. The method of any one of claims 1-71, wherein the subject exhibits a prolonged time to first dose reduction of the administered daily amount compared to subjects treated with 801 mg TID pirfenidone for the same treatment period.
73. 72. The method of any one of claims 1-71, wherein the subject exhibits a reduced number of dose reductions in the administered daily dose compared to subjects treated with 801 mg TID pirfenidone over the same treatment period.
74. 72. The method of any one of claims 1-71, wherein the subject exhibits a prolonged time to first treatment interruption or temporary cessation of treatment compared to subjects treated with 801 mg TID pirfenidone for the same treatment period.
75. 72. The method of any one of claims 1-71, wherein the subject exhibits a reduced number of treatment interruptions or temporary cessation of treatment compared to subjects treated with 801 mg TID pirfenidone for the same treatment period.
76. 72. The method of any one of claims 1-71, wherein the subject exhibits a prolonged time to treatment discontinuation compared to subjects treated with 801 mg TID pirfenidone for the same treatment period.
77. 77. The method of any one of claims 72 to 76, wherein the treatment period is at least 26 weeks.
78. 78. The method of any one of claims 1-77, wherein the subject shows improved treatment compared to a subject treated with 801 mg TID pirfenidone.
79. 79. The method of claim 78, wherein the improved treatment comprises a reduction in the number of one or more adverse events (AEs).
80. 80. The method of claim 78 or claim 79, wherein the improved treatment comprises a shortening of the duration of one or more adverse event(s) (AE).
81. 81. The method of any one of claims 78-80, wherein the one or more AEs are selected from nausea, vomiting, abdominal pain or bloating, dyspepsia, diarrhea, decreased appetite, constipation, headache, dizziness, somnolence, fatigue, drug intolerance, elevated AST, ALT, GGT, and hepatotoxicity.
82. 82. The method of any one of claims 78 to 81, wherein the improvement comprises a slowing of progression of respiratory dysfunction.
83. 83. The method of any one of claims 78-82, wherein the improvement comprises an increased time to respiratory dysfunction.
84. 84. The method of any one of claims 78-83, wherein the improvement comprises a slowing of progression of IPF.
85. 85. The method of one of claims 78 to 84, wherein the improvement comprises an increase in the time to progression of IPF.
86. 86. The method of claim 84 or claim 85, wherein the progression of IPF is determined by measuring the decline in FVC (mL).
87. 86. The method of claim 84 or claim 85, wherein the progression of IPF is determined by measuring a decline in FVCpp.
88. 88. The method of any one of claims 84 to 87, wherein the progression of IPF is measured over a treatment period of at least 26 weeks.
89. 89. The method of any one of claims 78-88, wherein the improvement comprises a decrease in the rate of decline in FVC (mL).
90. 90. The method of claim 89, wherein the percentage decline in FVC (mL) over a treatment period of at least 26 weeks is less than the percentage decline exhibited by subjects treated with 801 mg TID pirfenidone.
91. 89. The method of any one of claims 78 to 88, wherein the improvement comprises a decrease in the rate of decline of FVCpp.
92. 92. The method of claim 91, wherein the percentage decline in FVCpp over a treatment period of at least 26 weeks is less than the percentage decline exhibited by subjects treated with 801 mg TID pirfenidone.
93. The method of any one of claims 86 to 88, wherein progression of IPF is determined by a decline in FVCpp of 5% or more.
94. 94. The method of any one of claims 78-93, wherein the improvement comprises increased time to hospitalization for respiratory dysfunction compared to subjects treated with 801 mg TID pirfenidone.
95. 95. The method of claim 94, wherein the hospitalization is a first hospitalization.
96. 95. The method of claim 94, wherein the hospitalization is not a first hospitalization.
97. 97. The method of any one of claims 94 to 96, wherein the time to hospitalization due to respiratory dysfunction is measured over a treatment period of at least 26 weeks.
98. 98. The method of any one of claims 78-97, wherein the improvement is a reduction in the number of hospitalizations due to respiratory dysfunction compared to subjects treated with 801 mg TID pirfenidone.
99. 99. The method of claim 98, wherein the number of hospitalizations due to respiratory dysfunction is measured over a treatment period of at least 26 weeks.
100. 100. The method of any one of claims 78-99, wherein the improvement comprises a shorter length of hospital stay upon hospitalization for respiratory dysfunction compared to subjects treated with 801 mg TID pirfenidone.
101. 101. The method of claim 100, wherein the length of hospitalization (s) due to respiratory dysfunction is measured over a treatment period of at least 26 weeks.
102. 102. The method of any one of claims 78-101, wherein the improvement comprises an improvement in changes in one or more serum biomarkers associated with respiratory dysfunction compared to subjects treated with 801 mg TID pirfenidone.
103. 103. The method of claim 102, wherein the serum biomarker is collagen type 4.
104. The method of claim 102 or claim 103, wherein the serum biomarkers associated with respiratory dysfunction are measured over a treatment period of at least 26 weeks.
105. 105. The method of any one of claims 78-104, wherein the improvement comprises increased time to death from respiratory dysfunction compared to subjects treated with 801 mg TID pirfenidone.
106. The method of claim 105, wherein the time to death from respiratory dysfunction is measured over a treatment period of at least 26 weeks.
107. 107. The method of any one of claims 78-106, wherein the subject exhibits improvement in treatment as determined in one or more of the following: King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score; St. George's Respiratory Questionnaire (SGRQ-I) domain scores; EuroQol 5 Item (EQ5D) questionnaire score; and cough visual analog scale (VAS) compared to subjects treated with 801 mg TID pirfenidone.
108. 108. The method of claim 107, wherein the improvement in treatment is measured over a treatment period of at least 26 weeks.
109. A method of improving treatment for idiopathic pulmonary fibrosis (IPF) as compared to treatment with pirfenidone, comprising administering to a subject in need thereof a compound of the structure: 【Chemistry 5】 in a total daily dose of about 1650 mg to about 2500 mg of deuterium-enriched pirfenidone having the formula:
110. The method of claim 109, wherein the improved treatment is improved tolerability as determined by a reduced incidence of one or more gastrointestinal AEs and / or a reduced duration of one or more gastrointestinal AEs.
111. The method of claim 110, wherein the one or more gastrointestinal AEs are selected from nausea, vomiting, loss of appetite, and abdominal pain or bloating.
112. The method of claim 110 or claim 111, wherein the incidence of the one or more gastrointestinal AEs is reduced by at least 30%.
113. The method of any one of claims 109 to 112, wherein the improved treatment comprises improved tolerability compared to treatment with pirfenidone, as determined by a reduced incidence of one or more neurological AEs and / or a reduced duration of one or more neurological AEs.
114. 114. The method of claim 113, wherein the one or more nervous system AEs are selected from fatigue, headache, dizziness, and somnolence.
115. The method of claim 113 or claim 114, wherein the incidence of the one or more neurological AEs is reduced by at least 30%.
116. 116. The method of any one of claims 109-115, wherein the improved treatment comprises one or more of: a reduced incidence or frequency of dose reductions of the administered daily dose, a longer time to first dose reduction of the administered daily dose, a reduced incidence of treatment interruptions or temporary cessation of treatment, a longer time to first treatment interruptions or temporary cessation of treatment, and a reduced incidence of treatment discontinuation.
117. 117. The method of any one of claims 109 to 116, wherein the improvement in treatment is measured over at least 26 weeks of treatment.
118. The method of claim 116 or claim 117, wherein the improved treatment is an improvement compared to a subject treated with 801 mg TID pirfenidone for the same treatment period.
119. 119. The method of any one of claims 109 to 118, wherein the improvement is selected from slowing or delaying the progression of respiratory impairment, slowing or delaying the progression of IPF, reducing the rate of decline in FVC(mL), reducing the rate of decline in FVCpp, increasing the time to hospitalization due to respiratory impairment, reducing the number of hospitalizations due to respiratory impairment, decreasing the length of hospitalization (s) due to respiratory impairment, and increasing the time to death due to respiratory impairment.
120. 120. The method of claim 119, wherein the improvement in treatment is measured over at least 26 weeks of treatment.
121. 121. The method of claim 119 or claim 120, wherein the improved treatment is an improvement compared to a subject treated with 801 mg TID pirfenidone for the same treatment period.
122. 122. The method of any one of claims 109-121, wherein the subject shows improvement in treatment as measured in one or more of: King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score; St. George's Respiratory Questionnaire (SGRQ-I) domain scores; EuroQol 5 Item (EQ5D) questionnaire score; and cough visual analog scale (VAS).
123. 123. The method of claim 122, wherein the improvement in treatment is measured over at least 26 weeks of treatment.
124. 124. The method of any one of claims 122 or 123, wherein the improved treatment is an improvement compared to a subject treated with 801 mg TID pirfenidone for the same treatment period.
125. 125. The method of any one of claims 1 to 124, wherein the subject has idiopathic pulmonary fibrosis diagnosed by a physician based on the ATS / ERS / JRS / ALAT 2018 guidelines or based on a high-resolution computed tomography (HRCT) performed within 12 months of initiating treatment.
126. 126. The method of any one of claims 1-125, wherein the subject has a clinically meaningful decrease in hemoglobin-corrected DLCO of 30% or greater than the normal predicted value prior to initiation of treatment.
127. The method of any one of claims 1-126, wherein the subject has a FVC that is greater than or equal to 45% of predicted value before treatment begins.
128. 128. The method of any one of claims 1-127, wherein the subject has not received prior treatment for IPF.
129. The method of any one of claims 1 to 127, wherein the subject has had prior treatment for IPF.
130. 130. The method of claim 129, wherein the prior treatment for IPF is nintedanib.
131. 130. The method of claim 129, wherein the prior treatment for IPF is pirfenidone.
132. The method of claim 130 or claim 131, wherein the subject has had prior exposure to nintedanib or pirfenidone for less than 6 months.