Genotype and dose-dependent response to an asbti in patients with bile salt export pump deficiency

Abstract

Provided herein are methods for treating or ameliorating cholestatic liver disease in a subject in need thereof. The methods include administering an Apical Sodium-dependent Bile Acid Transport Inhibitor (ASBTI) to the subject. The methods include determining a genotype of the subject and predicting subject response to the ASBTI administration based upon the genotype. The methods further include determining, adjusting, or modulating a dose of the ASBTI administered to the subject based upon the genotype or upon measurements of clinically relevant disease parameters.

1 . A method for treating or ameliorating cholestatic liver disease in a subject in need thereof, wherein the subject has a bile salt export pump (BSEP) deficiency, the method comprising administering to the subject an Apical Sodium-dependent Bile Acid Transport Inhibitor (ASBTI). 
     
     
         2 . The method of  claim 1 , wherein the ASBTI 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 2 , wherein the ASBTI is maralixibat, or an alternative pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 2 , wherein the ASBTI is volixibat, or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 2 , wherein the ASBTI is odevixibat, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 2 , wherein the ASBTI is elobixibat, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 2 , wherein the ASBTI is GSK2330672, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the cholestatic liver disease is progressive familial intrahepatic cholestasis type 2 (PFIC 2), benign recurrent intrahepatic cholestasis (BRIC) or intrahepatic cholestasis of pregnancy (ICP), or biliary atresia. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein the subject has residual BSEP function. 
     
     
         10 . The method of  claims 1 - 9 , wherein the BSEP deficiency results in impaired or reduced bile flow or cholestasis. 
     
     
         11 . The method of any of  claims 1 - 10 , wherein an ABCB11 gene of the subject comprises a non-truncating mutation. 
     
     
         12 . The method of  claim 11 , wherein the ABCB11 gene comprises one or more of E297G, D482G, an alternative missense mutation, or a combination thereof. 
     
     
         13 . The method of  claim 11 , wherein the ABCB11 gene comprises an E297G or a D482G mutation, or both. 
     
     
         14 . The method of any of  claim 11  or  12 , wherein the ABCB11 gene comprises a missense mutation and not an E297G or D482G mutation. 
     
     
         15 . The method of any of  claims 1 - 13  further comprising determining a genotype of the subject. 
     
     
         16 . The method of  claim 15 , wherein determining the genotype comprises identifying and characterizing a mutation in the ABCB11 gene. 
     
     
         17 . The method of  claim 16  wherein the ABCB11 gene of the subject is characterized as comprising only non-truncating mutations. 
     
     
         18 . The method of  claim 1  comprising determining a ratio of serum 7α-hydroxy-4-cholesten-2-one (7αC4) concentration to serum bile acid (sBA) concentration (7αC4:sBA) prior to administering the ASBTI at a first dose level (baseline ratio), and further determining 7αC4:sBA after the ASBTI administration, wherein the ASBTI administration results in a 7αC4:sBA ratio about 2-fold or greater higher than the baseline 7αC4:sBA ratio. 
     
     
         19 . The method of  claim 18 , wherein if the 7αC4:sBA ratio begins to decrease or decreases to less than 2-fold or greater higher than baseline, a second dose level of the ASBTI is administered to the subject, wherein the second dose level is higher than the first dose level. 
     
     
         20 . The method of  claim 1 , comprising determining a ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA) prior to administering the ASBTI at a first dose level (baseline ratio), and further determining 7αC4:sBA after the ASBTI administration, wherein if the ASBTI administration fails to result in a 7αC4:sBA ratio about 2-fold or greater higher than the baseline 7αC4:sBA ratio, the subject is administered a second dose level of the ASBTI, wherein the second dose level is higher than the first dose level. 
     
     
         21 . The method of  claim 1 , further comprising modulating a dose of the ASBTI, the modulating comprising determining a ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA) prior to administering the ASBTI at a first dose level (baseline ratio), and further determining 7αC4:sBA after the ASBTI administration, wherein if the ASBTI administration fails to result in a 7αC4:sBA ratio about 2-fold or greater higher than the baseline 7αC4:sBA ratio the ASBTI is then administered at a second dose level that does result in a 7αC4:sBA ratio that is about a 2-fold or greater higher than the baseline ratio. 
     
     
         22 . The method of  claim 1 , further comprising modulating a dose of the ASBTI, the modulating comprising determining a ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA) prior to administering the ASBTI at a first dose level (baseline ratio), and further determining 7αC4:sBA after the ASBTI administration, wherein if a treating physician believes the ratio could be elevated beyond the current level with a higher dose level of the ASBTI, then the subject is administered the ASBTI at a second dose level that results in a 7αC4:sBA ratio that is higher than the baseline ratio. 
     
     
         23 . The method of any of  claims 19 - 22 , wherein the second dose is at least about twice and less than about five times the first dose. 
     
     
         24 . The method of any of  claims 1 - 23 , wherein the subject is a pediatric subject under 18 years of age. 
     
     
         25 . The method of  claim 24 , wherein the administration of the ASBTI results in improved growth of the subject relative to baseline growth. 
     
     
         26 . The method of  claim 25 , wherein the improved growth of the subject is measured as an increase in height z-score. 
     
     
         27 . The method of any of  claims 1 - 26 , wherein the ASBTI is administered at a daily dose of from about 140 μg/kg to about 1400 μg/kg. 
     
     
         28 . The method of  claim 27 , wherein the ASBTI is administered once daily. 
     
     
         29 . The method of  claim 27 , wherein the ASBTI is administered twice daily. 
     
     
         30 . The method of any of  claims 1 - 29 , wherein the ASBTI is administered at a daily dose of from about 5 mg/day to about 100 mg/day. 
     
     
         31 . The method of any of  claims 1 - 30 , wherein the ASBTI is administered regularly for a period of at least one year. 
     
     
         32 . The method of any of  claims 1 - 31 , wherein the ASBTI is administered regularly for a period of at least 4 years. 
     
     
         33 . The method of any of  claims 1 - 32 , 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. 
     
     
         34 . The method of  claim 33 , wherein the reduction in a symptom or a change in a disease-relevant laboratory measure comprises a reduction in sBA concentration, an increase in serum 7αC4 concentration, an increase in a ratio of serum 7αC4 concentration to 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, or a combination thereof. 
     
     
         35 . The method of  claim 34 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure is determined relative to a baseline level. 
     
     
         36 . The method of any of  claim 33  or  34 , wherein the subject is a pediatric subject under 18 years of age, and the reduction in a symptom or a change in a disease-relevant laboratory measure comprises an increase in growth. 
     
     
         37 . The method of any of  claims 1 - 36 , wherein the administration of the ASBTI results in an increase in serum 7αC4 concentration. 
     
     
         38 . The method of  claim 37 , wherein the serum 7αC4 concentration is increased from about 1.5-fold to about 40-fold relative to baseline. 
     
     
         39 . The method of any of  claims 1 - 38 , wherein the administration of the ASBTI results in an increase in a ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA). 
     
     
         40 . The method of  claim 39 , wherein the 7αC4:sBA is increased by from about 2-fold to about 5,000-fold relative to baseline. 
     
     
         41 . The method of any of  claims 1 - 40 , wherein the administration of the ASBTI results in an increase in fecal bile acids (fBA) of at least 100% relative to baseline. 
     
     
         42 . The method of any of  claims 1 - 41 , wherein the administration of the ASBTI results in a decrease in sBA concentration of at least about 70% relative to baseline. 
     
     
         43 . The method of any of  claims 1 - 42 , wherein the administration of the ASBTI results in a reduction in severity of pruritus. 
     
     
         44 . The method of  claim 43 , 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. 
     
     
         45 . The method of  claim 44 , wherein the administration of the ASBTI results in an ITCHRO(OBS) score of ≤1. 
     
     
         46 . The method of any of  claims 1 - 45 , wherein the administration of the ASBTI results in an increase in a quality of life inventory score. 
     
     
         47 . The method of  claim 46 , wherein the quality of life inventory score is a health-related quality of life (HRQoL) score. 
     
     
         48 . The method of  claim 46  or  47 , 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. 
     
     
         49 . The method of any of  claims 1 - 48 , wherein the serum bilirubin concentration is at pre-administration baseline level at about 4 months after first administration of the ASBTI. 
     
     
         50 . The method of any of  claims 1 - 49 , serum alanine aminotransferase (ALT) concentration is at pre-administration baseline level at about 4 months after first administration of the ASBTI. 
     
     
         51 . The method of any of  claims 1 - 50 , 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. 
     
     
         52 . The method of any of  claims 1 - 51 , wherein the administration of the ASBTI results in serum ALT concentration decreasing by at least about 10% relative to baseline. 
     
     
         53 . The method of any of  claims 1 - 52 , wherein the subject has biliary atresia or intrahepatic cholestasis of pregnancy. 
     
     
         54 . A method for predicting subject response to treatment of a cholestatic liver disease, wherein the treatment comprises administering to the subject in need of such treatment an ASBTI, the method comprising determining a genotype of the subject, and predicting subject response to the treatment based upon the genotype. 
     
     
         55 . The method of  claim 54 , wherein the ASBTI is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 55 , wherein the ASBTI is maralixibat, or an alternative pharmaceutically acceptable salt thereof. 
     
     
         57 . The method of  claim 55 , wherein the ASBTI is volixibat, or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The method of  claim 55 , wherein the ASBTI is odevixibat, or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 55 , wherein the ASBTI is elobixibat, or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of  claim 55 , wherein the ASBTI is GSK2330672, or a pharmaceutically acceptable salt thereof. 
     
     
         61 . The method of any of  claims 54 - 60 , wherein determining the genotype comprises determining a sequence of an ABCB11 gene. 
     
     
         62 . The method of  claim 61  further comprising identifying and characterizing a mutation of the ABCB11 gene. 
     
     
         63 . The method of  claim 62  further comprising predicting that the subject will not be responsive to administration of the ASBTI if the ABCB11 gene comprises a truncating mutation. 
     
     
         64 . The method of any of  claim 62  or  63  further comprising predicting that the subject will not be responsive to administration of the ASBTI if the ABCB11 gene comprises a mutation resulting in total loss of BSEP activity. 
     
     
         65 . The method of any of  claims 54 - 64  further comprising predicting that the subject will be responsive to administration of the ASBTI if the ABCB11 gene comprises mutations that result in residual BSEP activity and the ABCB11 gene comprises no mutations that result in absence of BSEP activity. 
     
     
         66 . The method of  claim 65 , wherein the ABCB11 gene comprises one or more of an E297G, D482G, an alternative missense mutation, or some combination thereof. 
     
     
         67 . The method of any of claims  54 -Error! Reference source not found., further comprising administering an ASBTI to the subject if the subject is predicted to be responsive to the administration of the ASBTI. 
     
     
         68 . The method of any of  claims 54 - 67 , wherein the subject has biliary atresia or intrahepatic cholestasis of pregnancy. 
     
     
         69 . A method for treating or ameliorating cholestatic liver disease in a subject in need thereof, wherein the subject has a BSEP deficiency, the method comprising:
 determining a genotype of the subject;   using the genotype of the subject to predict whether the subject will be or will not be responsive to treatment with an ASBTI; and   administering an ASBTI to the subject if the subject is predicted to be responsive to administration of the ASBTI.   
     
     
         70 . The method of  claim 69 , wherein determining the genotype comprises determining a sequence of an ABCB11 gene. 
     
     
         71 . The method of  claim 70  further comprising identifying and characterizing a mutation of the ABCB11 gene. 
     
     
         72 . The method of  claim 71  further comprising predicting that the subject will not be responsive to administration of the ASBTI if the ABCB11 gene comprises a truncating mutation. 
     
     
         73 . The method of  claim 71  further comprising predicting that the subject will not be responsive to administration of the ASBTI if the ABCB11 gene comprises a mutation resulting in total loss of BSEP activity. 
     
     
         74 . The method of  claim 71  further comprising predicting that the subject will be responsive to administration of the ASBTI if the ABCB11 gene comprises mutations that result in residual BSEP activity and the ABCB11 gene comprises no mutations that result in absence of BSEP activity. 
     
     
         75 . The method of any of  claim 71  or  74 , wherein the ABCB11 gene comprises one or more of an E297G, D482G, an alternative missense mutation, or some combination thereof. 
     
     
         76 . The method of  claim 69  further comprising determining a ratio of serum 7αC4 concentration to serum bile acid (sBA) concentration (7αC4:sBA) prior to administering the ASBTI at a first dose (baseline ratio), and further determining the 7αC4:sBA after the ASBTI administration. 
     
     
         77 . The method of  claim 76 , 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 about >2-fold higher than the baseline ratio. 
     
     
         78 . The method of  claim 76 , 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. 
     
     
         79 . The method of any of  claim 77  or  78 , wherein the second dose is at least about twice and less than about five times the second dose. 
     
     
         80 . The method of any of  claims 69 - 79 , wherein the subject is a pediatric subject under 18 years of age. 
     
     
         81 . The method of  claim 80 , wherein the administration of the ASBTI results in improved growth of the subject. 
     
     
         82 . The method of  claim 81 , wherein improved growth of the subject is measured as an increase in height z-score. 
     
     
         83 . The method of any of  claims 69 - 82 , wherein the ASBTI is administered at a daily dose of from about 140 μg/kg to about 1400 μg/kg. 
     
     
         84 . The method of any of  claims 69 - 83 , wherein the ASBTI is administered once daily. 
     
     
         85 . The method of any of  claims 69 - 84 , wherein the ASBTI is administered twice daily. 
     
     
         86 . The method of any of  claims 69 - 85 , wherein the ASBTI is administered at a dose of from about 5 mg/day to about 100 mg/day. 
     
     
         87 . The method of any of  claims 69 - 86 , wherein the ASBTI is administered regularly for a period of at least one year. 
     
     
         88 . The method of any of  claims 69 - 87 , wherein the ASBTI is administered regularly for a period of at least 4 years. 
     
     
         89 . The method of any of  claims 69 - 88  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. 
     
     
         90 . The method of  claim 89 , wherein the reduction in a symptom or a change in a disease-relevant laboratory measure comprises a reduction in sBA concentration, an increase in serum 7αC4 concentration, an increase in a ratio of serum 7αC4 concentration to 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, or a combination thereof. 
     
     
         91 . The method of  claim 90 , wherein the reduction in the symptom or a change in a disease-relevant laboratory measure is determined relative to a baseline level. 
     
     
         92 . The method of any of  claim 89  or  90 , wherein the subject is a pediatric subject under 18 years of age and the reduction in a symptom or a change in a disease-relevant laboratory measure comprises an increase in growth. 
     
     
         93 . The method of any of  claims 69 - 92 , wherein the administration of the ASBTI results in an increase in serum 7αC4 concentration. 
     
     
         94 . The method of  claim 93 , wherein the serum 7αC4 concentration is increased from about 1.5-fold to about 40-fold relative to baseline. 
     
     
         95 . The method of  claim 93 , wherein the serum 7αC4 concentration is increased by at least 100% relative to baseline. 
     
     
         96 . The method of any of  claims 69 - 95 , wherein the administration of the ASBTI results in an increase in a ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA). 
     
     
         97 . The method of  claim 96 , wherein 7αC4:sBA is increased by from about 2-fold to about 5,000-fold relative to baseline. 
     
     
         98 . The method of any of  claims 69 - 97 , wherein the administration of the ASBTI results in an increase in fBA of at least 100% relative to baseline. 
     
     
         99 . The method of claim any of  claims 69 - 98 , wherein the administration of the ASBTI results in a decrease in sBA concentration of at least about 70% relative to baseline. 
     
     
         100 . The method of any of  claims 69 - 99 , wherein the administration of the ASBTI results in a reduction in severity of pruritus. 
     
     
         101 . The method of  claim 100 , 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 relative to baseline. 
     
     
         102 . The method of  claim 100  or  101 , wherein the administration of the ASBTI results in an ITCHRO(OBS) score of ≤1. 
     
     
         103 . The method of any of  claims 69 - 102 , wherein the administration of the ASBTI results in an increase in a quality of life inventory score. 
     
     
         104 . The method of  claim 103 , wherein the quality of life inventory score is a health-related quality of life (HRQoL) score. 
     
     
         105 . The method of any of  claim 103  or  104 , wherein the quality of life inventory score is a Pediatric Quality of Life Inventory (PedsQL) score. 
     
     
         106 . The method of  claim 105 , wherein the PedsQL score is increased by at least 10% relative to baseline. 
     
     
         107 . The method of any of  claims 69 - 106 , wherein serum bilirubin concentration is at pre-administration baseline level at about 4 months after first administration of the ASBTI. 
     
     
         108 . The method of any of  claims 69 - 107 , wherein serum ALT concentration is at pre-administration baseline level at about 4 months after first administration of the ASBTI. 
     
     
         109 . The method of any of  claims 69 - 108 , wherein serum ALT concentration, serum AST concentration, and serum bilirubin concentration being are within a normal range at about 4 months after first administration of the ASBTI. 
     
     
         110 . The method of any of  claims 69 - 109 , wherein the administration of the ASBTI results in serum ALT concentration decreasing by at least about 10% relative to baseline. 
     
     
         111 . The method of any of  claims 69 - 110 , wherein the subject has biliary atresia or intrahepatic cholestasis of pregnancy. 
     
     
         112 . The method of any of  claims 69 - 111 , wherein the subject has PFIC 2.