المؤلفون: Abdelmalek, Manal F., Sanyal, Arun J., Nakajima, Atsushi, Neuschwander-Tetri, Brent A., Goodman, Zachary D., Lawitz, Eric J., Harrison, Stephen A., Jacobson, Ira M., Imajo, Kento, Gunn, Nadege, Halegoua-DeMarzio, Dina, Akahane, Takemi, Boone, Bradly, Yamaguchi, Masayuki, Chatterjee, Arkendu, Tirucherai, Giridhar S., Shevell, Diane E., Du, Shuyan, Charles, Edgar D., Loomba, Rohit

المساهمون: Bristol-Myers Squibb Co Summit, Bristol-Myers Squibb

المصدر: Clinical Gastroenterology and Hepatology ; volume 22, issue 1, page 113-123.e9 ; ISSN 1542-3565

مصطلحات موضوعية: Gastroenterology, Hepatology

الإتاحة: https://doi.org/10.1016/j.cgh.2023.04.012Test
https://api.elsevier.com/content/article/PII:S1542356523003117?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1542356523003117?httpAccept=text/plainTest

المؤلفون: Loomba, Rohit, Sanyal, Arun J., Nakajima, Atsushi, Neuschwander-Tetri, Brent A., Goodman, Zachary D., Harrison, Stephen A., Lawitz, Eric J., Gunn, Nadege, Imajo, Kento, Ravendhran, Natarajan, Akahane, Takemi, Boone, Bradly, Yamaguchi, Masayuki, Chatterjee, Arkendu, Tirucherai, Giridhar S., Shevell, Diane E., Du, Shuyan, Charles, Edgar D., Abdelmalek, Manal F.

المساهمون: Bristol-Myers Squibb Co Summit, Bristol-Myers Squibb

المصدر: Clinical Gastroenterology and Hepatology ; volume 22, issue 1, page 102-112.e9 ; ISSN 1542-3565

مصطلحات موضوعية: Gastroenterology, Hepatology

الإتاحة: https://doi.org/10.1016/j.cgh.2023.04.011Test
https://api.elsevier.com/content/article/PII:S1542356523003105?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1542356523003105?httpAccept=text/plainTest

المؤلفون: Taylor-Weiner, Amaro, Pokkalla, Harsha, Han, Ling, Jia, Catherine, Huss, Ryan, Chung, Chuhan, Elliott, Hunter, Glass, Benjamin, Pethia, Kishalve, Carrasco-Zevallos, Oscar, Shukla, Chinmay, Khettry, Urmila, Najarian, Robert, Taliano, Ross, Subramanian, G, Myers, Robert, Wapinski, Ilan, Khosla, Aditya, Resnick, Murray, Montalto, Michael, Anstee, Quentin, Wong, Vincent, Trauner, Michael, Lawitz, Eric, Harrison, Stephen, Okanoue, Takeshi, Romero-Gomez, Manuel, Goodman, Zachary, Loomba, Rohit, Beck, Andrew, Younossi, Zobair

المصدر: Hepatology. 74(1)

مصطلحات موضوعية: Biopsy, Deep Learning, Humans, Image Processing, Computer-Assisted, Liver, Liver Cirrhosis, Non-alcoholic Fatty Liver Disease, Randomized Controlled Trials as Topic, Reproducibility of Results, Severity of Illness Index

الوصف: BACKGROUND AND AIMS: Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response. APPROACH AND RESULTS: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression. CONCLUSIONS: Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/64b8h3cvTest

المؤلفون: Jayakumar, Saumya, Middleton, Michael S, Lawitz, Eric J, Mantry, Parvez S, Caldwell, Stephen H, Arnold, Hays, Diehl, Anna Mae, Ghalib, Reem, Elkhashab, Magdy, Abdelmalek, Manal F, Kowdley, Kris V, Djedjos, C Stephen, Xu, Ren, Han, Ling, Subramanian, G Mani, Myers, Robert P, Goodman, Zachary D, Afdhal, Nezam H, Charlton, Michael R, Sirlin, Claude B, Loomba, Rohit

المصدر: Journal of Hepatology. 70(1)

مصطلحات موضوعية: Digestive Diseases, Hepatitis, Substance Misuse, Clinical Research, Chronic Liver Disease and Cirrhosis, Liver Disease, Biomedical Imaging, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Oral and gastrointestinal, Good Health and Well Being, Adolescent, Adult, Aged, Benzamides, Biopsy, Disease Progression, Dose-Response Relationship, Drug, Elasticity Imaging Techniques, Female, Humans, Imidazoles, Injections, Subcutaneous, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Pyridines, ROC Curve, Reproducibility of Results, Treatment Outcome, Young Adult, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Hepatic steatosis, Non-invasive tests, Liver biopsy, Clinical Sciences, Public Health and Health Services, Gastroenterology & Hepatology

الوصف: Background & aimsNon-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH.MethodsWe analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS).ResultsAmong 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value.ConclusionsThese preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH.Lay summaryLiver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

الوصول الحر: https://escholarship.org/uc/item/96b1p0vjTest

المؤلفون: Lawitz, Eric J, Coste, Angie, Poordad, Fred, Alkhouri, Naim, Loo, Nicole, McColgan, Bryan J, Tarrant, Jacqueline M, Nguyen, Tuan, Han, Ling, Chung, Chuhan, Ray, Adrian S, McHutchison, John G, Subramanian, G Mani, Myers, Robert P, Middleton, Michael S, Sirlin, Claude, Loomba, Rohit, Nyangau, Edna, Fitch, Mark, Li, Kelvin, Hellerstein, Marc

المصدر: Clinical Gastroenterology and Hepatology. 16(12)

مصطلحات موضوعية: Liver Disease, Digestive Diseases, Clinical Research, Biomedical Imaging, Chronic Liver Disease and Cirrhosis, Hepatitis, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Oral and gastrointestinal, Acetyl-CoA Carboxylase, Administration, Oral, Adolescent, Adult, Aged, Elasticity Imaging Techniques, Enzyme Inhibitors, Female, Humans, Isobutyrates, Lipogenesis, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Oxazoles, Prospective Studies, Pyrimidines, Treatment Outcome, Young Adult, TIMP1, ALT, Drug, Clinical Trial, Treatment, Fatty Liver, Clinical Sciences, Gastroenterology & Hepatology

الوصف: Background & aimsIncreased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.MethodsIn an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis.ResultsThe contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF.ConclusionIn an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.

الوصول الحر: https://escholarship.org/uc/item/4j57x1h1Test

المؤلفون: Loomba, Rohit, Kayali, Zeid, Noureddin, Mazen, Ruane, Peter, Lawitz, Eric J, Bennett, Michael, Wang, Lulu, Harting, Eliza, Tarrant, Jacqueline M, McColgan, Bryan J, Chung, Chuhan, Ray, Adrian S, Subramanian, G Mani, Myers, Robert P, Middleton, Michael S, Lai, Michelle, Charlton, Michael, Harrison, Stephen A

المصدر: Gastroenterology. 155(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Hepatitis, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Biomedical Imaging, Liver Disease, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Acetyl-CoA Carboxylase, Biomarkers, Carnitine, Double-Blind Method, Elasticity Imaging Techniques, Fatty Liver, Female, Humans, Isobutyrates, Liver Cirrhosis, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Oxazoles, Pyrimidines, De Novo Lipogenesis, Magnetic Resonance Elastography, Tissue Inhibitor of Metalloproteinase 1, Effects, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics

الوصف: Background & aimsDe novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH.MethodsWe analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy.ResultsA relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976.ConclusionsIn a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/83g1c15zTest

المؤلفون: Ratziu, Vlad, Harrison, Stephen A., Loustaud-Ratti, Veronique, Bureau, Christophe, Lawitz, Eric, Abdelmalek, Manal, Alkhouri, Naim, Francque, Sven, Girma, Hugo, Darteil, Raphael, Couchoux, Harold, Wolf, Myles, Sanyal, Arun, Vonderscher, Jacky, Scalfaro, Pietro

المصدر: 0168-8278 ; Journal of hepatology

مصطلحات موضوعية: Human medicine

الوصف: Background & Aims: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).Methods: This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive pla-cebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12.Results: One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively.Conclusions: In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit.Clinical trial number (EudraCT): 2018-003119-22.ClinicalTrials.gov Identifier: NCT03812029.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of ...

العلاقة: info:eu-repo/semantics/altIdentifier/isi/000952650200001

الإتاحة: https://doi.org/10.1016/J.JHEP.2022.10.023Test
https://hdl.handle.net/10067/1961480151162165141Test
https://repository.uantwerpen.be/docstore/d:irua:17383Test

المؤلفون: Romero-Gómez, Manuel, Lawitz, Eric, Shankar, R Ravi, Chaudhri, Eirum, LH Lam, Raymond, Skrypnyk, Igor, Bassan, Isaac, Скрипник, Ігор Миколайович

مصطلحات موضوعية: Non-alcoholic fatty liver disease, steatosis, hepatic lipogenesis

الوصف: Methods: This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of >− 10% at screening were randomized 1:1 to efinopegdutide 10 mg or semaglutide 1 mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. Results: Among 145 randomized participants (efinopegdutide n = 72, semaglutide n = 73), 33.1% had T2DM. At baseline, mean BMI was 34.3 kg/m2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8–78.7]) than with semaglutide (42.3% [90% CI 36.5–48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p = 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events.

العلاقة: A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease / M. Romero-Gómez, E. Lawitz, I. Skrypnyk [et al.] // Journal of Hepatology. – 2023. – Vol. 78. – P. 1–10.; http://repository.pdmu.edu.ua/handle/123456789/21443Test; https://doi.org/10.1016/j.jhep.2023.05.013Test

الإتاحة: https://doi.org/10.1016/j.jhep.2023.05.013Test
http://repository.pdmu.edu.ua/handle/123456789/21443Test

المؤلفون: Qosa, Hisham, de Oliveira, Claudia H. M. C., Cizza, Giovanni, Lawitz, Eric J., Colletti, Nicholas, Wetherington, Jeffrey, Charles, Edgar D., Tirucherai, Giridhar S.

المصدر: Clinical and Translational Science ; volume 16, issue 10, page 1791-1802 ; ISSN 1752-8054 1752-8062

الوصف: BMS‐986263 is a retinoid‐conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen‐specific chaperone protein involved in fibrosis development. This is a phase I, open‐label, two‐part study evaluating pharmacokinetics and safety of BMS‐986263 in participants with hepatic impairment (HI). Part 1 ( n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age‐ and body mass index (BMI)‐matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age‐ and BMI‐matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS‐986263 infusion. Compared with normal‐matched participants, geometric mean area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration (AUC (0‐T) ) and AUC from zero to infinity (AUC (INF) ) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal‐matched group. Overall, single‐dose BMS‐986263 was generally safe and well‐tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS‐986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure‐safety/efficacy relationship becomes available.

الإتاحة: https://doi.org/10.1111/cts.13581Test

المؤلفون: Newsome, Philip N., Sanyal, Arun J., Neff, Guy, Schattenberg, Jörn M., Ratziu, Vlad, Ertle, Judith, Link, Jasmin, Mackie, Alison, Schoelch, Corinna, Lawitz, Eric

المساهمون: Boehringer Ingelheim

المصدر: Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Non-alcoholic steatohepatitis (NASH) is a progressive, inflammatory liver disease with no approved pharmacological treatment. This Phase IIa, double-blind, placebo-controlled, multicentre trial (ClinicalTrials.gov: NCT03166735) investigated pharmacodynamics and safety of BI 1467335, an amine oxidase copper-containing 3 (AOC3) inhibitor, in adults with NASH from Europe and North America. Participants from 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland were randomised (2:1:1:1:2; 27 July 2017 to 14 June 2019) to daily oral BI 1467335 1 mg ( n = 16), 3 mg ( n = 16), 6 mg ( n = 17), 10 mg ( n = 32) or placebo ( n = 32) for 12 weeks, with follow-up to Week 16. Primary endpoint was AOC3 activity relative to baseline (%), 24 hours post-dose after 12 weeks’ treatment. Secondary biomarker endpoints included changes from baseline at Week 12 in alanine aminotransferase (ALT) and caspase-cleaved cytokeratin 18 (CK-18 caspase). Mean AOC3 activities relative to baseline at Week 12: 90.4% (placebo; n = 32), 26.5% (1 mg; n = 16), 10.4% (3 mg; n = 16), 5.0% (6 mg; n = 16), 3.3% (10 mg; n = 32). These changes indicated that BI 1467335 dose-dependently inhibited AOC3 activity; ≥3 mg doses achieved >80% inhibition ( < 20% activity) at Week 4. At Week 12 following doses of BI 1467335 ≥ 3 mg, ALT and CK-18 caspase decreased dose-dependently. All tested BI 1467335 doses were well tolerated, with no clinically relevant treatment-emergent safety signals. BI 1467335 strongly inhibited AOC3 in participants with NASH, with doses ≥3 mg dose-dependently reducing the levels of liver injury biomarkers, ALT and CK-18. This trial was registered with ClinicalTrials.gov (NCT03166735) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2016-000499-83).

الإتاحة: https://doi.org/10.1038/s41467-023-42398-wTest
https://www.nature.com/articles/s41467-023-42398-w.pdfTest
https://www.nature.com/articles/s41467-023-42398-wTest