Treatment comprising fxr agonists
An agonist, dosing technology, applied in the field of farnesoid X receptor agonists, in the field of treatment or prevention of fibrotic or sclerotic diseases or disorders, to achieve low side effects, support compliance, and high therapeutic efficacy.
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example 1
[0161] Example 1: A 2-week study in cynomolgus monkeys treated with FXR agonists
[0162] 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.
[0163] Table 1. Study design.
[0164]
[0165] 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 ).
[0166] 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
[0167] Example 2: In vitro human hepatocytes treated with FXR agonists
[0168] 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.
[0169] 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
[0171] Example 3 Subjects with NASH and fibrosis (stage 2 or 3) were functionally assessed according to the NASH CRN histology score. Clinical studies on efficacy, safety and tolerability.
[0172] main target : Demonstration of the efficacy of zopifexole as assessed by histological improvement after 48 weeks of treatment in subjects with NASH and stage 2 or 3 fibrosis.
[0173] secondary goal :
[0174] - Improvement in fibrosis by at least one stage after 48 weeks of treatment in which NASH has not worsened
[0175] - NASH resolution after 48 weeks of treatment in which fibrosis has not worsened
[0176] - Fibrosis improved by at least one stage
[0177] - Improvement in fibrosis by at least two stages after 48 weeks of treatment in which NASH has not worsened
[0178] - Weight loss compared to baseline after 48 weeks of treatment
[0179] -Changes in liver fat content after 48 weeks of treatment
[0180] - To determine the relationship between investigational t...
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