Combination treatment of liver diseases using FXR agonists
A liver disease and agonist technology, applied in drug combinations, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., to achieve the effects of supporting compliance, high therapeutic efficacy, and low side effects
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example 1
[0219] Example 1: A 2-week study in cynomolgus monkeys treated with FXR agonists
[0220] In a 2-week study in cynomolgus monkeys treated with an FXR agonist (LJP305), the rate of total bile acid production and the main subpopulations of different bile acids were measured, as figure 1 shown and described in Table 1.
[0221] Table 1. Study design.
[0222]
[0223] Although total bile acids decreased ( figure 2 ), the ratio of CA to CDCA bile acids changed over time, with a severe decrease in CA ( image 3 ), but accompanied by an increase in CDCA bile acids ( Figure 4 ).
[0224] The most effective way to avoid this inhibition of Cyp7A1 and subsequent activation of the alternative pathway is to administer a FXR agonist at a time when Cyp7A1 enzymatic activity is at its lowest, thereby minimizing FXR-mediated inhibition of Cyp1A1. Because the activity of this enzyme in humans is at a minimum at night, administration of FXR agonists at night (from about 6 pm to abou...
example 2
[0225] Example 2: In vitro human hepatocytes treated with FXR agonists
[0226] In humans, FXR agonist treatment is associated with lipid abnormalities, including increases in peripheral LDL. Increased cholesterol in hepatocytes is associated with a counter-action mechanism that reduces LDL receptors on the cell surface. This reduction of LDL receptors on the surface of hepatocytes will eventually lead to an increase in circulating LDL; a phenotype observed clinically.
[0227] Figure 5 It was shown that in vitro (using human hepatocytes in vitro), FXR agonists such as obeticholic acid (OCA) and cilofexol (GS-9674) reduced LDL uptake by hepatocytes in a dose-dependent manner. Those data suggest that blockade of Cyp7A1 and the bile acid pathway leads to a peripheral increase in LDL. To mitigate the increase in peripheral LDL, we hypothesized that treating a subject at night (from about 6pm to about 12pm, eg from about 8pm to about 11pm, preferably about 9pm) would reduce ...
example 3
[0229] Example 3: Subjects with NASH and fibrosis (Stage 2 or 3) according to NASH CRN histology score Clinical studies of efficacy, safety and tolerability.
[0230] Primary objective: To demonstrate the efficacy of the combination of zopifexo and lipagliflozin as assessed by histological improvement after 48 weeks of treatment in subjects with NASH and stage 2 or 3 fibrosis.
[0231] Secondary goals:
[0232] - Improvement in fibrosis by at least one stage after 48 weeks of treatment in which NASH has not worsened
[0233] - NASH resolution after 48 weeks of treatment in which fibrosis has not worsened
[0234] - Fibrosis improved by at least one stage
[0235] - Improvement in fibrosis by at least two stages after 48 weeks of treatment in which NASH has not worsened
[0236] - Weight loss compared to baseline after 48 weeks of treatment
[0237] -Changes in liver fat content after 48 weeks of treatment
[0238] - To determine the relationship between investigational ...
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