US2022160726A1PendingUtilityA1
Methods for treating cholestasis
Est. expiryFeb 12, 2039(~12.6 yrs left)· nominal 20-yr term from priority
C12Q 2600/156C12Q 2600/106C12Q 1/6883A61K 31/7042A61K 38/10A61K 31/554A61P 1/16A61K 31/4995A61P 17/04C12N 15/11G01N 33/6893G01N 2800/085C12N 15/113A61K 38/05
68
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Claims
Abstract
Provided herein are methods for treating cholestasis in a subject having a liver disease. The method includes administering to the subject an Apical Sodium-dependent Bile Acid Transporter (ASBTI). More specifically, the present invention relates to methods for treating cholestasis in a subject where the method includes administering an ASBTI to a subject at a dose of at least 10 μg/kg/day.
Claims
exact text as granted — not AI-modified1 . A method for treating cholestatic liver disease in a subject comprising administering to the subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), wherein the ASBTI is administered in an amount of from about 10 μg/kg/day to about 1400 μg/kg/day.
2 . The method of claim 1 , wherein the ASBTI is wherein the ASBTI is
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the ASBTI is maralixibat, or an alternative pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein the ASBTI is volixibat, or a pharmaceutically acceptable salt thereof.
5 . The method of claim 1 , wherein the ASBTI is odevixibat, or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein the ASBTI is elobixibat, or a pharmaceutically acceptable salt thereof.
7 . The method of claim 1 , wherein the ASBTI is GSK2330672, or a pharmaceutically acceptable salt thereof.
8 . The method of any of claims 1 - 7 , wherein the cholestatic liver disease is a pediatric cholestatic liver disease that results in below normal growth, height, or weight.
9 . The method of any of claims 1 to 8 , wherein the cholestatic liver disease is selected from progressive familial intrahepatic cholestasis (PFIC), Alagille Syndrome (ALGS), primary sclerosing cholangitis (PSC), biliary atresia, intrahepatic cholestasis of pregnancy (ICP), or primary biliary cholangitis (PBC).
10 . The method of any of claims 1 to 9 , wherein the cholestatic liver disease is biliary atresia.
11 . The method of any of claims 1 to 9 , wherein the cholestatic liver disease is ICP.
12 . The method of any of claims 1 to 9 , wherein the cholestatic liver disease is PFIC.
13 . The method of claim 12 , wherein the ASBTI is odevixibat.
14 . The method of claim 12 , wherein the ASBTI is maralixibat.
15 . The method of any of claims 12 - 14 , wherein the PFIC is selected from PFIC type 1, PFIC type 2 and PFIC type 3.
16 . The method of any of claims 12 - 15 , wherein the PFIC is PFIC type 2.
17 . The method of claim 16 , wherein the subject has a non-truncating mutation in ABCB11 gene.
18 . The method of any of claims 1 to 17 , wherein the subject is a pediatric subject.
19 . The method of any of claims 1 to 18 , wherein the ASBTI is administered once daily (QD).
20 . The method of any of claims 1 to 18 , wherein the ASBTI is administered twice daily (BID).
21 . The method of any of claims 1 to 20 , wherein the ASBTI is administered in an amount of from about 140 μg/kg/day to about 1400 μg/kg/day.
22 . The method of any of claims 1 to 21 , wherein the ASBTI is administered in an amount of from about 280 μg/kg/day to about 1400 μg/kg/day.
23 . The method of any of claims 12 to 22 , wherein the administration of the ASBTI results in a reduction in a symptom or a change in a disease-relevant laboratory measure of the cholestatic liver disease that is maintained for at least one year.
24 . The method of claim 23 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure comprises a reduction in sBA concentration, an increase in serum 7α-hydroxy-4-cholesten-3-one (7αC4) concentration, an increase in a ratio of serum 7αC4 concentration to serum bile acids (sBA) concentration (7αC4:sBA), a reduction in pruritis, an increase in a quality of life inventory score, an increase in a quality of life inventory score related to fatigue, an increase in growth, or a combination thereof.
25 . The method of claim 24 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure is determined relative to a baseline level.
26 . The method of any of claims 23 to 25 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure comprises an increase in growth.
27 . The method of claim 26 , wherein the increase in growth of the pediatric subject is measured as an increase in height Z-score or weight Z-score.
28 . The method of any of claims 1 to 27 , wherein the administration of the ASBTI results in an increase in serum 7αC4 concentration.
29 . The method of claim 28 , wherein the serum 7αC4 concentration is increased from about 1.5-fold to about 40-fold relative to baseline.
30 . The method of claim 28 , wherein the serum 7αC4 concentration is increased by at least 100% relative to baseline.
31 . The method of any of claims 1 to 30 , wherein the administration of the ASBTI results in an increase in a ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA).
32 . The method of claim 31 , wherein the 7αC4:sBA is increased by from about 2-fold to about 5,000-fold relative to baseline.
33 . The method of claim 31 or 32 , further comprising administering a second dose of the ASBTI, wherein the second dose is greater than the first dose, if after the administration of the first dose of the ASBTI the 7αC4:sBA is not maintained at about >2-fold higher than the baseline ratio.
34 . The method of claim 31 or 32 , further comprising administering a second dose of the ASBTI, wherein the second dose is greater than the first dose, if the 7αC4:sBA initially increases by at least >2-fold higher than the baseline ratio and then begins to decrease back to the baseline ratio.
35 . The method of any of claims 1 to 34 , wherein the administration of the ASBTI results in a decrease in sBA concentration of at least about 70% relative to baseline.
36 . The method of any of claims 1 to 35 , wherein the administration of the ASBTI results in a reduction in severity of pruritus.
37 . The method of claim 36 , wherein the reduction in severity of pruritis is measured as a reduction of at least 1.0 in an observer-reported itch reported outcome (ITCHRO(OBS)) score.
38 . The method of any of claims 36 or 37 , wherein the administration of the ASBTI results in an ITCHRO(OBS) score of ≤1.
39 . The method of any of claims 1 to 38 , wherein the administration of the ASBTI results in an increase in a quality of life inventory score, or in a quality of life inventory score related to fatigue.
40 . The method of claim 39 , wherein the quality of life inventory score is a health-related quality of life (HRQoL) score related to fatigue.
41 . The method of claims 39 or 40 , wherein the quality of life inventory score is a Pediatric Quality of Life Inventory (PedsQL) score, and wherein the PedsQL score is increased by at least 10% relative to baseline.
42 . The method of any of claims 1 to 41 , wherein serum bilirubin concentration is at about pre-administration baseline level at about 4 months after first administration of the ASBTI.
43 . The method of any of claims 1 to 42 , wherein serum alanine aminotransferase (ALT) concentration is at about pre-administration baseline level at about 4 months after first administration of the ASBTI.
44 . The method of any of claims 1 to 43 , wherein serum aspartate aminotransferase (AST) concentration, and serum bilirubin concentration are within a normal range at about 4 months after first administration of the ASBTI.
45 . The method of any of claims 1 to 44 , wherein the administration of the ASBTI results in serum ALT concentration decreasing by at least about 10% relative to baseline.
46 . The method of any of claims 1 to 9 , wherein the cholestatic liver disease is ALGS.
47 . The method of any of claim 46 , wherein the subject is a pediatric subject.
48 . The method of any of claims 1 and 46 to 47 , wherein the ASBTI is administered once daily (QD).
49 . The method of any of claims 1 and 46 to 47 , wherein the ASBTI is administered twice daily (BID).
50 . The method of any of claims 1 and 46 to 49 , wherein the ASBTI is administered in an amount of about 140 μg/kg/day to about 1400 μg/kg/day.
51 . The method of any of claims 1 and 46 to 50 , wherein the ASBTI is administered in an amount of about 280 μg/kg/day to about 1400 μg/kg/day.
52 . The method of any of claims 46 to 505 , wherein the administration of the ASBTI results in a reduction in a symptom or a change in a disease-relevant laboratory measure of the cholestatic liver disease that is maintained for at least 6 months.
53 . The method of claim 52 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure comprises a reduction in sBA concentration, an increase in serum 7αC4 concentration, a reduction in pruritis, an increase in a quality of life inventory score, an increase in a quality of life inventory score related to fatigue, a reduction in xanthoma score, an increase in growth, or a combination thereof.
54 . The method of claim 53 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure is determined relative to a baseline level.
55 . The method of any of claims 52 to 54 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure comprises an increase in growth.
56 . The method of claim 55 , wherein the increase in growth of the pediatric subject is measured as an increase in height Z-score or weight Z-score.
57 . The method of any of claims 52 to 55 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure is maintained for at least 2 years.
58 . The method of any of claims 46 to 57 , wherein the administration of the ASBTI results in a reduction of intensity of pruritus.
59 . The method of claim 58 , wherein an ITCHRO(OBS) score of the subject is reduced by at least 40% relative to baseline.
60 . The method of any of claims 58 or 59 , wherein a CSS score of the subject is reduced by at least 50% relative to baseline.
61 . The method of any of claims 58 to 60 , wherein the subject has an ITCHRO(OBS) score of ≤1 on at least 50% of days after 6 months.
62 . The method of any of claims 58 to 61 , wherein the administration of the ASBTI results in a maintained and progressive decrease in severity and frequency of pruritus over time.
63 . The method of any of claims 46 to 62 , wherein the administration of the ASBTI results in a reduction in sBA concentration of at least 30% by 18 weeks.
64 . The method of claim 63 , wherein the administration of the ASBTI results in a reduction in sBA concentration of at least 50%.
65 . The method of any of claims 46 to 64 , wherein administration of the ASBTI coincides with a positive correlation between reduction in sBA concentration and reduction in severity of pruritus.
66 . The method of any of claims 46 to 65 , wherein the administration results in a xanthoma score of the subject being reduced by at least 25%.
67 . The method of any of claims 46 to 66 , wherein the administration of the ASBTI results in an increase in a quality of life inventory score.
68 . The method of claim 67 , wherein the quality of life inventory score is a health-related quality of life (HRQoL) score.
69 . The method of claims 67 or 68 , wherein the quality of life inventory score is a Pediatric Quality of Life Inventory (PedsQL) score, and wherein the PedsQL score is increased by at least 10% relative to baseline.
70 . The method of any of claims 46 to 69 , wherein the administration of the ASBTI results in a reduction in serum cholesterol concentration of at least 15% by 18 weeks.
71 . The method of any of claims 46 to 70 , wherein the administration of the ASBTI results in an increase in serum 7αC4 concentration of at least 50% by about 18 weeks.
72 . The method of any of claims 46 to 71 , wherein the ASBTI is administered for up to 3 years.
73 . The method of any of claims 46 to 72 , wherein the ASBTI is administered for up to 4 years.
74 . The method of any of claims 1 to 9 , wherein the cholestatic liver disease is PSC and the ASBTI is volixibat, or a pharmaceutically acceptable salt thereof.
75 . The method of claim 1 or 74 , wherein the subject is an adult.
76 . The method of any of claims 1 and 74 to 75 , wherein the ASBTI is administered once daily (QD).
77 . The method of any of claims 1 and 74 to 75 , wherein the ASBTI is administered twice daily (BID).
78 . The method of any of claims 1 and 74 to 77 , wherein the ASBTI is administered in an amount of about 0.5 mg/day to about 100 mg/day.
79 . The method of any of claims 74 to 78 , wherein the administration of the ASBTI results in a reduction in a symptom or a change in a disease-relevant laboratory measure of the cholestatic liver disease that is maintained for at least four weeks.
80 . The method of claim 79 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure comprises a reduction in sBA concentration, an increase in serum 7αC4 concentration, a reduction in serum autotaxin concentration, a reduction in pruritis, an increase in a quality of life inventory score, an increase in a quality of life inventory score related to fatigue, or a combination thereof.
81 . The method of claim 80 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure is determined relative to a baseline level.
82 . The method of any of claims 79 to 81 , wherein a degree of the reduction in the symptom or a change in a disease-relevant laboratory measure demonstrates a positive correlation with a baseline ITCHRO score of the subject.
83 . The method of claim 82 , wherein the degree of the reduction in the symptom or a change in a disease-relevant laboratory measure is greater if the subject has a baseline ITCHRO score of at least four than if the subject has a baseline ITCHRO score of less than 4.
84 . The method of any of claims 74 to 83 , wherein the administration of the ASBTI results in a reduction in severity of pruritus.
85 . The method of claim 84 , wherein an ITCHRO score of the subject is reduced by at least 40% relative to baseline by 14 weeks.
86 . The method of claim 85 , wherein the ITCHRO score of the subject is reduced by at least 60% relative to a baseline ITCHRO score of 4 or higher.
87 . The method of any of claims 74 to 86 , wherein the administration of the ASBTI results in a reduction in sBA concentration of at least 30% relative to baseline.
88 . The method of claim 87 , wherein sBA concentration is reduced by at least 45% relative to baseline if the subject has a baseline ITCHRO score of at least 4.
89 . The method of any of claims 74 - 88 , wherein the administration of the ASBTI results in a reduction in total serum cholesterol concentration of at least 10 mg/dL.
90 . The method of claim 89 , wherein reduction in total serum cholesterol concentration is at least 12.5 mg/dL if the subject has a baseline ITCHRO score of at least 4.
91 . The method of any of claims 74 to 90 , wherein the administration of the ASBTI results in a reduction in serum LDL cholesterol concentration of at least 5%.
92 . The method of any of claims 74 to 91 , wherein the administration of the ASBTI results in a reduction in serum LDL cholesterol concentration of at least 10 mg/dL.
93 . The method of any of claims 74 to 92 , wherein the administration of the ASBTI results in an increase in serum 7αC4 concentration of at least 30% relative to baseline.
94 . The method of any of claims 74 to 93 , wherein the administration of the ASBTI results in a reduction in serum autotaxin concentration of at least 50% if the subject has a baseline ITCHRO score of at least 4.
95 . The method of any of claims 74 to 94 , wherein the administration of the ASBTI results in a reduction in serum autotaxin concentration of at least 10% by week 6 and 20% by week 14.
96 . The method of any of claims 74 to 95 , wherein the administration of the ASBTI does not result in a significant change from baseline in serum conjugated bilirubin concentration if the subject has a baseline ITCHRO score of at least 4.
97 . The method of any of claims 74 to 96 , wherein the administration of the ASBTI does not result in a significant change from baseline in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof.
98 . The method of any of claims 1 to 97 , wherein by day 28 of administration the subject's fecal bile acids (fBA) excretion increases by at least 250 μmol.
99 . The method of any of claims 1 to 98 , wherein upon day 7 of administration the subject's fBA excretion increases by at least 1,000 μmol.
100 . The method of any of claims 1 to 99 , wherein upon day 7 of administration of the ASBTI the subject's fBA excretion increases by at least 1.5-fold relative to baseline.
101 . The method of any of claims 1 to 100 , wherein administration of the ASBTI results in an at least 4-fold increase in fBA excretion relative to baseline.
102 . The method of any of claims 1 to 101 , wherein administration of the ASBTI results in a dose-dependent increase in fBA excretion.Cited by (0)
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