WO2022101853A1 - Procédé de détermination de la fibrose hépatique - Google Patents
Procédé de détermination de la fibrose hépatique Download PDFInfo
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- WO2022101853A1 WO2022101853A1 PCT/IB2021/060522 IB2021060522W WO2022101853A1 WO 2022101853 A1 WO2022101853 A1 WO 2022101853A1 IB 2021060522 W IB2021060522 W IB 2021060522W WO 2022101853 A1 WO2022101853 A1 WO 2022101853A1
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- collagen
- liver
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- steatosis
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H30/00—ICT specially adapted for the handling or processing of medical images
- G16H30/40—ICT specially adapted for the handling or processing of medical images for processing medical images, e.g. editing
Definitions
- This disclosure relates to a method for measuring and characterizing liver fibrosis.
- This disclosure also relates to a method for measuring and characterizing changes in an amount of collagen present in a liver over a course of treatment. More specifically, the amount of collagen present is characterized in a manner that is independent of the presence of hepatic steatosis.
- this disclosure relates to the use of a farnesoid X receptor agonist (FXR agonist), such as tropifexor, for diagnosing, treating or preventing fibrotic or cirrhotic diseases or disorders, e.g. liver diseases or disorders.
- FXR agonist farnesoid X receptor agonist
- Non-alcoholic fatty liver disease is the most common chronic liver disease at present a ⁇ ecting ⁇ 25% of the adult population worldwide.
- NAFLD non-alcoholic steatohepatitis
- Liver fibrosis is the excessive accumulation of extracellular matrix proteins enriched in cross-linked collagen type I/III. Fibrosis in the liver is the hallmark of most chronic liver disease.
- liver diseases include chronic hepatitis B and C virus infections, alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and autoimmune liver disease.
- the natural course of NAFLD includes three consecutive phases: non-alcoholic fatty liver with simple steatosis; non-cirrhotic NASH and NASH with cirrhosis, which are associated with progressively increasing mortality risk and no approved drug therapy at present.
- An amount of collagen present in a patient’s liver can be used to determine a severity of the liver fibrosis condition and to track changes in the patient’s condition over the course of a treatment regime.
- Liver biopsy (the extraction of a small tissue sample from the liver) has traditionally been regarded as the gold standard for evaluation of fibrosis progress or regression.
- the amount of collagen present in the patient’s liver can be characterized by collagen proportional area (CPA).
- CPA is the proportion of an area occupied by collagen out of the total area of a cross-section of the hepatic tissue in microscopy liver biopsy images (Eq (1)).
- the total tissue area includes not only collagen area but also hepatic fatty areas.
- SHG/TPEF second harmonic generation/two photon excitation fluorescence
- the SHG/TPEF-based technology has also been used to monitor structural change in collagen at all stages of liver fibrosis. Further, the SHG/TPEF-based microscopy technology has also been used in the quantificaiton of hepatic steatosis and as a monitoring tool of steatosis development. See Quantification of Hepatic Steatosis in Chronic Liver Disease Using Novel Automated Method of Second Harmonic Generation and Two-Photon Excited Fluorescence (2019, Scientific Reports); and https://www.histoindex.com/product-and-services/. The traditional method of calculating the CPA takes into account the presence of steatosis in the hepatic tissue.
- tropifexor reduces hepatic steatosis (the accumulation of large vacuoles of triglyceride fat in the liver cells) prior to or simultaneously reducing liver fibrosis.
- inflammatory and fibrosis modulators that may not directly reduce hepatic steatosis are being considered as combination partners with anti-inflammatory and anti- fibrotic agents specifically designed to reduce hepatic steatosis.
- the present disclosure provides a method for quantifying liver collagen, independent of hepatic steatosis.
- the present disclosure provides a method for quantifying changes in liver collagen, independent of changes in hepatic steatosis.
- FIGS.1A – 1D show cross-sectional views of different liver tissue samples
- FIGS.2A – 2B show schematic diagrams of exemplary tissue areas before and after treatment
- FIG.3 shows a diagram illustrating different regions of a liver tissue sample that are listed in FIG.3
- FIGS.4A – 4F show graphs illustrating the data shown in Table 1 in the various locations depicted in FIG.3.
- DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following description is presented to enable any person skilled in the art to make and use the embodiments, and is provided in the context of a particular application and its requirements.
- the corrected CPA that excluses hepatic steatosis areas can be quantified by: 1) determining an area of biopsy tissue; 2) determining an area of collagen in a biopy tissue; 3) determining an area of hepatic steatosis in a biopy tissue; 4) subtracting that area of hepatic steatosis from 3) from the area of biopsy tissue from 1) to give a corrected tissue area; and 5) divide the area of collagen from 2) by the corrected tissue are from 4) to give a corrected CPA.
- an area of collagen for a particular cross-section of a liver tissue sample can be quantified by capturing an image of the cross-section with a nonlinear optical imaging system that utilizes optical phenomenon such as two-photon excitation (TPE) and second harmonic generation (SHG) to collect useful cellular information and generate a co- localized image of the cross-section.
- TPE two-photon excitation
- SHG second harmonic generation
- the imaging platform generally includes a platform for deposition of the test specimen; an electromagnetic light source coupling to the platform to direct a radiation at an excitation wavelength to an interested region of the liver tissue sample, the radiation resulting in emission of a first and a second electromagnetic signals respectively caused by TPE of excitable material and SHG of optically non-linear materials in the collagen fibers in the liver tissue sample; sensors being arranged to respectively real-time record the emitted first and second electromagnetic signals and convert the received first and second electromagnetic signals separately into a first digital signal and a second digital signal; an optical assembly for manipulating the radiation directed to the liver tissue sample and the emitted first and second electromagnetic signals prior to having the first and second electromagnetic signals recorded by the sensors; a microprocessor unit being configured to use the first and second electromagnetic signals in generating a co-localized image having a set of image properties and being indicative of spatial distribution of the collagen fibers in the interested region, quantify one or more scalar features and distribution features of the co-localized image to generate quantified result for each s
- the test specimen is trimmed to a thickness of 1 to 5 microns and free from any staining.
- the imaging platform can also be configured to work with stained test specimen.
- the microprocessor unit associated with the imaging system leverages machine learning algorithms and/or deep neural networks to extract and analyze distribution and/or scalar features of the co-localized image created thus quantifying the collagen fibers deposited and/or correlating a diseased state to the test specimen being imaged.
- the distribution or intensity of the second electromagnetic signal corresponds to brightness of collagen fibers in the co-localized image generated and is relatively indicative of the amount of collagen fibers deposited in one or more regions of interest of the liver tissue sample.
- the external structure, shape or pattern of the other cellular structures located in the interested region can be revealed by intensity and/or distribution of the first electromagnetic signal, which is complement to the second electromagnetic signal in the co-localized image.
- gray level co-occurrence matrix is employed in the disclosed system for texture classification of the identified collagen fibers that correlation and dissimilarity of the spots sampled from the co- localized image are preferably computed and plotted in the feature space to determine the class. Once characterization of all the detected collagen fibers is complete the area of each detected collagen fiber can be aggregated together to determine a total area of the collagen in the test specimen.
- Steatosis Measurement and Analysis The contents of Quantification of Hepatic Steatosis in Chronic Liver Disease Using Novel Automated Method of Second Harmonic Generation and Two-Photon Excited Fluorescence (2019, Scientific Reports) are fully incorporated by reference. Certain specific embodiments are discussed below.
- Steatosis in the liver tissue sample can also be measured using a nonlinear optical imaging system.
- the liver tissue sample is the same liver tissue sample used for collagen measurement.
- the liver tissue sample is a different liver tissue sample (e.g., a different biopsy section) than that used for collagen measurement, but from the same liver biopsy.
- One example of a commercially available imaging system is the Genesis produced by HistoIndex Pte. Ltd. of Singapore.
- the steatosis analysis can be performed on the same imagery used to perform the collagen measurement and analysis.
- the imaging system requires the biopsy be stained, the steatosis analysis will be performed on a first slices of a liver specimen and the collagen analysis is performed on a second slice of the liver specimen as close to and similar to the first slice as possible.
- the lipids within the biopsy are often leeched out. Consequently, the steatosis analysis focuses on the identification of fat vacuoles left after the lipids are leeched out and distinguishing the fat vacuoles from tissue artefacts that may create non-steatic holes, such as the edges of the biopsy where there is more tissue fragmentation.
- the area of the identified fat vacuoles is then aggregated to determine a total steatosis or fat area for the biopsy cross-section.
- the steatosis analysis can be performed by an automated computing system that begins by ignoring any empty holes in the tissue sample that are determined to be smaller than a predefined threshold size where the threshold is defined by the minimum area of established fat vacuoles.
- the automated computing system continues to a second step in which it uses a decision tree constructed using a classification and regression tree (CART) model to identify the rest of the empty holes as being associated with a fact vacuole or not.
- the CART model can be built based on a training image database.
- the training image database is constructed by identifying all the holes in the training image database including fat vacuoles, vessels and cracks.
- FIGS. 1A - 1D show cross-sectional views of different liver tissue samples.
- FIG. 1A shows a liver tissue sample illustrating a progressive septa state in which fine collagen fiber runs between inflammatory cells in a parallel formation.
- FIG. 1B shows a more advanced stage of fibrosis referred to as an established septa state.
- FIG. 1C a regressive septa state
- septa is squeezed into thin and dense strings by newly regenerated hepatocytes from both sides.
- FIG. 1D a broken septa state
- the septa are infiltrated by newly regenerated hepatocytes and collagen fiber runs around hepatocytes in circular formation.
- FIGS. 2A - 2B are used to demonstrate one of the inventive concepts of the current disclosure.
- FIGS. 2A - 2B represent exemplary tissue area before and after treatment.
- FIG. 2A shows an exemplary tissue area from biopsy before treatment, including the collagen area, hepatic fat area and the rest of the tissue area. During treatment, hepatic fat area becomes reduced. For simplicity, the collagen area and the rest of tissue area are kept constant in FIG. 2B to highlight effect of steatosis reduction.
- Eq (2) shows how Eq (1) can be adjusted to make the calculation independent of fat area.
- the cCPA being constant is consistent with the common understanding of this example in that no change in collagen area has taken place.
- Table 1 below shows exemplary statistical data illustrating mean changes, as between the onset of treatment and the completion of a 48-week treatment trial period, in collagen contents for 97 different subjects in various regions of the liver tissue samples.
- the 97 subjects were distributed across three groups of patients that include a placebo group, a group receiving 140mcg doses of Tropifexor and a group receiving 200mcg doses of Tropifexor.
- the data in Table 1 also shows statistically significant differences between changes in the amount of collagen against placebo using the uncorrected CPA calculation and using the corrected CPA calculation.
- Table 1 Summary of CPA % change from baseline to end of treatment
- FIG. 3 illustrates locations of the various regions of the liver referenced in Table 1.
- liver biopsies can include areas of tissue that contain a portal tract (PT) and a central vein (CV).
- PT portal tract
- CV central vein
- a region of the biopsy within 100 microns of the portal tract is referred to as the periportal region (PP).
- PP periportal region
- PC pericentral region
- PS peri-sinusoidal region
- FIG. 3 also identifies the periportal, peri-sinusoidal and pericentral regions as Zone 1, Zone 2 and Zone 3, respectively.
- FIGS. 4A-4F graphically illustrate the data shown in Table 1. In particular, FIG.
- FIGS. 4A illustrates how the cCPA method of characterizing collagen and thus the change in collagen areas shows a greater percentage change from the placebo group than the percentage change using the uncorrected CPA method.
- the reduction in collage area is most pronounced in Zone 2 (the peri-sinusoidal region) depicted in FIG. 4B.
- Reductions in collagen area calculated using the cCPA method are also more pronounced relative to the uncorrected CPA method in the periportal (Zone 1) and pericentral (Zone 3) regions, as shown in FIGS.4C and 4D respectively.
- FIG. 4B illustrates how using the cCPA method on data from Zone 2 (the peri-sinusoidal region) associated with patients taking the 200 mcg dosage shows a 20% higher reduction in collagen than patients taking a placebo.
- the uncorrected calculation only shows an 8% reduction in collagen over patients taking the placebo in Zome 2.
- the corrected CPA method that excluses hepatic steatosis areas can be calculated by: 1) determining an area of biopsy tissue; 2) determining an area of collagen in a biopy tissue; 3) determining an area of hepatic steatosis in a biopy tissue; 4) subtracting that area of hepatic steatosis from 3) from the area of biopsy tissue from 1) to give a corrected tissue area; and 5) divide the area of collagen from 2) by the corrected tissue are from 4) to give a corrected CPA.
- the present invention further allows an accurate stratification of liver fibrosis and a more meaningful evaluation of NASH treatment efficacy.
- the invention may be particularly useful in conjunction with biomarker tests focused on steatosis (e.g., ⁇ 2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT, fasting glucose, triglycerides, LDL-C and HDL-C) and hepatic fat fraction (HFF) by MRI.
- biomarker tests focused on steatosis e.g., ⁇ 2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT, fasting glucose, triglycerides, LDL-C and HDL-C
- HFF hepatic fat fraction
- NASH therapeutics – inflammatory and fibrosis modulators such as CCR2/5 or ASK1 inhibitors
- metablolic modulators such as PPAR agonists, ACC, SGLT1/2, GLP1, or KHK inhibitors
- lipid modulators such as DGAT2, THR-6 inhibitors
- multimodal agents e.g., FXR inhibitors
- NASH treatment may include reduction of steatosis in addition to resolution of fibrosis.
- the therapeutics include the following: FXR agonist, ⁇ V ⁇ 1 integrin inhibitor, Steroyl-CoA desaturase-1 (SCD-1) inhibitor (e.g., arachidyl amido cholanoic acid (AramcholTM)), THR- ⁇ agonist (e.g., MGL-3196 (Resmetirom), VK-2809, MGL-3745 (Madrigal)), galectin-2 inhibitor (e.g., GR-MD-02/ Belapectin), PPAR agonist (e.g., saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, pioglitazone, IVA337 (Inventiva), CER-002 (Cerenis), MBX-8025 (Seladelpar)), GLP-1 agonist (e.g., exenatide, liraglutide, semaglutide, NC-101 (
- the FXR agonist as used herein refers, for example, to compounds disclosed in: WO2016/096116, WO2016/127924, WO2017/218337, WO2018/024224, WO2018/075207, WO2018/133730, WO2018/190643, WO2018/214959, WO2016/096115, WO2017/118294, WO2017/218397, WO2018/059314, WO2018/085148, WO2019/007418, CN109053751, CN104513213, WO2017/128896, WO2017/189652, WO2017/189663, WO2017/189651, WO2017/201150, WO2017/201152, WO2017/201155, WO2018/067704, WO2018/081285, WO2018/039384, WO2015/138986, WO2017/078928, WO2016/081918, WO2016/103037, and WO2017/143134.
- the FXR agonist is preferably selected from: tropifexor, nidufexor, obeticholic acid (6 ⁇ - ethyl-chenodeoxycholic acid), cilofexor (GS-9674, Px-102), INT-767, AKN-083, 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid, a pharmaceutically acceptable salt, prodrug and/or ester thereof and/or an amino acid conjugate thereof, e.g. meglumine salt.
- the therapeutic agent is a SGLT1/2 inhibitor, e.g.
- the ⁇ V ⁇ 1 integrin inhibitor is PLN-1474.
- the present invention is not limited to fibrosis quantification.
- the cCPA method is applicable to quantification of any liver histological feature when heptatic fat quantitation is implicated.
- the present invention provides a method of diagnosing a liver condition by determining liver fibrosis comprising determining a collagen proportional area in the area of interest of the liver tissue based on Eq (2).
- a method of diagnosis or of quantification of fibrosis comprising - obtaining a patient biological sample, e.g.
- a biopsy sample - conducting a digital image analysis (DIA), and - estimating a collagen area, wherein the estimating of the collagen area is provide by dividing the area of collagen present by a portion of the total tissue area that excludes hepatic steatosis areas (e.g according to Eq (2)).
- DIA digital image analysis
- estimating of collagen area is quantitative.
- FXR Farnesoid X receptor
- FXR Farnesoid X receptor
- 6a The FXR agonist for use according to any of Embodiments 3a to Embodiment 5a, wherein the FXR agonist is selected from tropifexor, obeticholic acid, nidufexor, cilofexor, TERN-101, EDP-305, PXL007, AGN242266 and MET409. 7a.
- a method of treating, preventing, or ameliorating liver diseases e.g.
- NASH comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent that affects at least one of liver fibrosis and hepatic steatosis, wherein the therapeutic agent is administered at a therapeutically effective dose to said subject, and wherein initially said subject receives treatment for 2 to 6 months and thereafter the subject remains on treatment for as long as the liver disease does not progress and/or the therapeutic agent is satisfactorily tolerated.
- a method of treating, preventing, or ameliorating liver diseases e.g.
- NASH comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent that affects at least one of liver fibrosis and hepatic steatosis, wherein the therapeutic agent is administered at a therapeutically effective dose to said subject, and wherein initially said subject receives treatment for 2 to 6 months and thereafter the subject remains on treatment until the treatment shows an improvement in fibrosis, and wherein the improvement in fibrosis is determined by measuring the area of collagen according to equation Eq (2). 3b.
- a method for the stabilization or lessening the severity or progression of a liver disease e.g.
- NASH comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent that affects at least one of liver fibrosis and hepatic steatosis, wherein the therapeutic agent is administered at a therapeutically effective dose to said subject, and wherein initially said subject receives treatment for 2 to 6 months and thereafter the subject remains on treatment until the treatment shows an improvement in fibrosis, and wherein the improvement in fibrosis is determined by measuring the area of collagen according to equation Eq (2). 4b.
- a method for slowing, arresting, or reducing the development of a chronic liver disease or disorder e.g.
- NAFLD, NASH, liver fibrosis or PBC in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent that affects at least one of liver fibrosis and hepatic steatosis, wherein the therapeutic agent is administered at a therapeutically effective dose to said subject, and wherein initially said subject receives treatment for 2 to 6 months and thereafter the subject remains on treatment until the treatment shows an improvement in fibrosis, and wherein the improvement in fibrosis is determined by measuring the area of collagen according to equation Eq (2). 5b.
- a method of treating, preventing, or ameliorating liver diseases e.g.
- NASH comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent that affects at least one of liver fibrosis and hepatic steatosis, wherein the therapeutic agent is administered at a therapeutically effective dose to said subject, and wherein initially said subject receives treatment for 2 to 6 months and thereafter the subject remains on treatment for as long as said patient has at least one stage improvement of fibrosis when measured using digital pathology methodology, wherein the digital pathology methodology includes: - obtaining a patient biological sample, e.g.
- biopsy sample - conducting a digital image analysis (DIA), and - estimating of a collagen area, wherein the estimating of the collagen area is provide by dividing the area of collagen present by a portion of the total tissue area that does not include hepatic steatosis areas (Eq (2)).
- DIA digital image analysis
- estimating of the collagen area is provide by dividing the area of collagen present by a portion of the total tissue area that does not include hepatic steatosis areas (Eq (2)).
- Eq (2) hepatic steatosis areas
- NASH comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent that affects at least one of liver fibrosis and hepatic steatosis, wherein the therapeutic agent is administered at a therapeutically effective dose to said subject, and wherein initially said subject receives treatment for 2 to 6 months and thereafter the subject remains on treatment for as long as the reduction in % of the fat in the liver of said subject is at least 30%, e.g. the change in % of fat as measured by hepatic fat fraction (HFF) by MRI (MRI-PDFF) is at least 30%. 7b.
- HFF hepatic fat fraction
- MRI-PDFF MRI-PDFF
- NAS Activity
- SAF Activity and Fibrosis
- ALT levels in said subject improvement in subject's Steatosis
- AST levels in said subject improvement in subject's ballooning
- NAFLD resolution NAFLD resolution without worsening of fibrosis
- reduction of fibrosis without NAFLD worsening reduction of ALT levels in said subject
- reduction of AST levels in said subject reduction of HbA1c levels in said subject
- lack of subject's progression to Cirrhosis inhibiting progression of Non-Alcoholic Fatty Liver Disease (NAFLD) and/or Non-Alcoholic Steatohepatitis (NASH), or any combination thereof.
- NAFLD Non-Alcoholic Fatty Liver Disease
- NASH Non-Alcoholic Steatohepatitis
- SCD-1 inhibitor e.g., arachidyl amido cholanoic acid (AramcholTM)
- THR- ⁇ agonist e.g., MGL-3196 (Resmetirom), VK-2809, MGL-3745 (Madrigal)
- galectin-2 inhibitor e.g., GR- MD-02/ Belapectin
- PPAR agonist e.g., saroglitazar, seladelpar, elafibranor, lanifibranor, lobeglitazone, pioglitazone, IVA337 (Inventiva), CER-002 (Cerenis), MBX-8025 (Seladelpar)
- GLP-1 agonist e.g., exenatide, liraglutide, semaglutide, NC-101 (Naia Metabolic), G-49 (Astrazeneca)
- Embodiment 12b comprising administering once daily to said subject a therapeutically effective amount of a FXR agonist, wherein the FXR agonist is administered in the evening. 14b.
- obeticholic acid is administered at a daily dose of about 5 mg, of about 10 mg, of about 15 mg, of about 20 mg, of about 25 mg, of about 30 mg, of about 40 mg or of about 50 mg. 15b.
- the method according to Embodiment 12b, wherein the FXR agonist is tropifexor. 16b.
- the method according to Embodiment 15b wherein tropifexor is administered at a daily dose of about 90 mcg to about 250 mcg, e.g. of about 140 mcg to about 200 mcg. 17b.
- NASH non-alcoholic steatohepatitis
- Tropifexor is administered at a dose (e.g. daily dose) of about 90 mcg to about 250 mcg, e.g. of about 140 mcg to about 200 mcg.
- Obeticholic acid is administered at a daily dose of about 5 mg, of about 10 mg, of about 15 mg, of about 20 mg, of about 25 mg, of about 30 mg, of about 40 mg or of about 50 mg.
- the FXR agonists as defined herein are provided for the treatment of a disease or disorder mediated by FXR, e.g. a liver disease or disorder, e.g. a chronic liver disease or disorder, e.g.
- a disease or disorder selected from the group consisting of cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis of pregnancy, parenteral nutrition-associated cholestasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familiar cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile duct injury, gallstones, liver cirrhosis, alcohol-induced cirrhosis, cystic fibrosis-associated liver disease (CFLD), bile duct obstruction, cholelithiasis, liver fibrosis, renal fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic nephropathy, colitis, newborn jaundice, prevention of kernicterus, veno-occlusive
- a pharmaceutical unit dosage form composition comprising about 90 mcg, about 140 mcg, about 150 mcg, about 160 mcg, about 170 mcg, about 180 mcg, about 190 mcg, about 200 mcg g, about 210 mcg, about 220 mcg, about 230 mcg, about 240 mcg or about 250 mcg of tropifexor suitable for oral administration once daily, in the evening, or shortly before or at bedtime.
- Such unit dosage form compositions may be in a form selected from a liquid, a tablet, a capsule.
- these unit dosage form compositions are for use in treating a chronic liver disease, e.g. non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile duct injury, gallstones, liver cirrhosis, alcohol- induced cirrhosis, cystic fibrosis, bile duct obstruction, cholelithiasis, liver fibrosis, e.g. for use in treating non-alcoholic steatohepatitis (NASH), e.g. for use in treating phenotypic non- alcoholic steatohepatitis (NASH).
- NASH non-alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- NASH non-alcoholic steatohepatitis
- NASH non-alcoholic steatohepatitis
- NASH non-alcoholic steatohepatitis
- drug-induced bile duct injury gallstones
- the FXR agonists as defined herein are provided for preventing or delaying progression of a chronic liver disease or disorder to a more advanced stage or a more serious condition thereof, e.g. for preventing or delaying progression of a chronic liver disease or disorder selected from the group consisting of NAFLD, NASH, hepatic fibrosis and PBC.
- a chronic liver disease or disorder selected from the group consisting of NAFLD, NASH, hepatic fibrosis and PBC.
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Abstract
L'invention concerne des procédés de caractérisation précise d'une quantité de collagène présent dans le foie d'un patient au cours d'un traitement contre la fibrose hépatique. Du fait que les traitements de la NASH pourraient réduire la stéatose hépatique, le procédé selon la présente invention exclut la stéatose hépatique dans la quantification de la zone de proportion de collagène dans le foie. Cela permet d'éviter que les variations de la stéatose hépatique affectent les déterminations précises des variations de la quantité de collagène.
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WO2023204768A1 (fr) * | 2022-04-21 | 2023-10-26 | Histoindex Pte Ltd | Méthode et système d'évaluation d'une intervention thérapeutique |
WO2023249562A1 (fr) * | 2022-06-22 | 2023-12-28 | Histoindex Pte Ltd | Procédé et système d'évaluation de changement de fibrose hépatique |
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