- |||||||||| Farxiga (dapagliflozin) / Ono Pharma, AstraZeneca
Clinical, Review, Journal: Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. (Pubmed Central) - Feb 2, 2022
At the time of writing this review, only Zydus Cadila's new drug application for Saroglitazar had been approved (2020) for NASH therapy in India...Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon...Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come.
- |||||||||| bile acid cholic acid (INT-777) / Intercept
Preclinical, Journal: Reversal of Alopecia Areata, Osteoporosis follow treatment with Activation of Tgr5 in mice. (Pubmed Central) - Feb 1, 2022
The study utilized a comparison control group design with four groups of wild-type group, wild-type+INT777 group, Tgr5-/- group, and Tgr5-/-+INT777 group...After treating with INT777, the appearance of alopecia areata and bone microstructure has improved. Immunohistochemistry and qPCR analysis showed that activation of Tgr5 can down-regulate the express of JAK1, STAT3, IL-6, TNF-α, and VEGF.These findings indicate that activation of Tgr5 mediated amelioration of alopecia areata and osteoporosis by down-regulated JAK1-STAT3 signaling pathway.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Trial termination: COBALT: Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (clinicaltrials.gov) - Jan 31, 2022
P4, N=334, Terminated,
Immunohistochemistry and qPCR analysis showed that activation of Tgr5 can down-regulate the express of JAK1, STAT3, IL-6, TNF-α, and VEGF.These findings indicate that activation of Tgr5 mediated amelioration of alopecia areata and osteoporosis by down-regulated JAK1-STAT3 signaling pathway. Active, not recruiting --> Terminated; The DMC made the recommendation to not pursue further enrollment given the lack of feasibility for this post-marketing study as designed.
- |||||||||| bile acid cholic acid (INT-777) / Intercept
Journal: The function of zebrafish gpbar1 in antiviral response and lipid metabolism. (Pubmed Central) - Jan 27, 2022
Similar to mammalian GPBAR1, zebrafish gpbar1 contains similar domain composition, shows a dose-dependent activation by bile acids including INT777, LCA, DCA, CDCA and CA, and can be induced by viral infection...The lipidomic analysis showed that zebrafish gpbar1 activation in ZF4 cells resulted a change of glycerophospholipids, but none of bile acids nor their derivatives, which were different from mammalian GPBAR1. All together, these results firstly demonstrate the conserved antiviral role of gpbar1 and its function in regulating glycerophospholipids metabolism in teleost.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: miR-199a-5p inhibits the Expression of ABCB11 in Obstructive Cholestasis. (Pubmed Central) - Jan 27, 2022
We also show treatment of mice after CBDL with the potent nuclear receptor FXR agonist obeticholic acid (OCA) significantly increased Abcb11 mRNA and protein and decreased miR-199a-5p expression...In CBDL mice treated with OCA, NcoR1 recruitment to the miR199a-2 FXRE was maintained at levels found in sham operated mice. In conclusion, we demonstrate that miR-199a-5p is involved in regulating ABCB11/Abcb11 expression, is aberrantly upregulated in obstructive cholestasis, and is downregulated by the FXR agonist obeticholic acid.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Review, Journal: A Current Understanding of Bile Acids in Chronic Liver Disease. (Pubmed Central) - Jan 26, 2022
We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients (clinicaltrials.gov) - Jan 25, 2022
P2, N=13, Active, not recruiting,
In the near future, further evidence in this area might help clinicians better detect and manage liver diseases. Recruiting --> Active, not recruiting | N=20 --> 13 | Trial completion date: Jan 2022 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Oct 2022
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Clinical, Journal: Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. (Pubmed Central) - Jan 15, 2022
This study of UDCA-treated PBC patients showed that, compared to placebo, OCA increased the transport of the conjugated bile acid tracer C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. Thereby OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Trial completion date, Trial initiation date, Trial primary completion date: Obeticholic Acid for Prevention in Barrett's Esophagus (clinicaltrials.gov) - Jan 13, 2022
P2, N=30, Not yet recruiting,
Thereby OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Trial completion date: Sep 2023 --> Apr 2024 | Initiation date: Dec 2021 --> Apr 2022 | Trial primary completion date: Sep 2023 --> Apr 2024
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Preclinical, Journal: Induction of fecal cholesterol excretion is not effective for the treatment of hyperbilirubinemia in Gunn rats. (Pubmed Central) - Jan 11, 2022
Trial completion date: Sep 2023 --> Apr 2024 | Initiation date: Dec 2021 --> Apr 2022 | Trial primary completion date: Sep 2023 --> Apr 2024 Increasing fecal cholesterol excretion is not effective to treat unconjugated hyperbilirubinemia.This is the first time a potential relation between transintestinal excretion of cholesterol and unconjugated bilirubin is investigated.Transintestinal excretion of cholesterol and unconjugated bilirubin do not seem to be quantitatively linked.Unlike intestinal fatty acids, cholesterol cannot "capture" unconjugated bilirubin to increase its excretion.These results add to our understanding of ways to improve and factors regulating unconjugated bilirubin disposal in hyperbilirubinemic conditions.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Preclinical, Journal: Disordered farnesoid X receptor signaling is associated with liver carcinogenesis in Abcb11-deficient mice. (Pubmed Central) - Jan 4, 2022
Administration of the FXR agonist obeticholic acid reduced liver injury and tumor incidence in Abcb11 mice...The cholestatic liver injury and liver tumors developed in Abcb11 mice are associated with increased FXR antagonist BAs and thereby decreased activation of FXR. FXR activation might be a therapeutic strategy in ABCB11 deficiency diseases.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Discussion (Capital Suite 2) - Jan 4, 2022 - Abstract #EASLILC2022EASL_ILC_204;
Understanding the mechanistic basis of PBC may hold the key for improving available treatments and reducing morbidity and mortality for patients. Learning objectives gaining an overview of the current treatment options in primary biliary cholangitisgaining insights into the unmet clinical needs in managing primary biliary cholangitisexploring the pros and cons of PBC being a primary autoimmune diseaseexploring the pros and cons of PBC being a primary secretory disease that promotes cholestasis and subsequent immune reaction
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Secretory defect Speaker (Capital Suite 2) - Jan 4, 2022 - Abstract #EASLILC2022EASL_ILC_203;
Understanding the mechanistic basis of PBC may hold the key for improving available treatments and reducing morbidity and mortality for patients. Learning objectives gaining an overview of the current treatment options in primary biliary cholangitisgaining insights into the unmet clinical needs in managing primary biliary cholangitisexploring the pros and cons of PBC being a primary autoimmune diseaseexploring the pros and cons of PBC being a primary secretory disease that promotes cholestasis and subsequent immune reaction
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Autoimmune Speaker (Capital Suite 2) - Jan 4, 2022 - Abstract #EASLILC2022EASL_ILC_202;
Understanding the mechanistic basis of PBC may hold the key for improving available treatments and reducing morbidity and mortality for patients. Learning objectives gaining an overview of the current treatment options in primary biliary cholangitisgaining insights into the unmet clinical needs in managing primary biliary cholangitisexploring the pros and cons of PBC being a primary autoimmune diseaseexploring the pros and cons of PBC being a primary secretory disease that promotes cholestasis and subsequent immune reaction
- |||||||||| Ocaliva (obeticholic acid) / Intercept
PBC: primary autoimmune disease or primary secretory defect? (Capital Suite 2) - Jan 4, 2022 - Abstract #EASLILC2022EASL_ILC_201;
Understanding the mechanistic basis of PBC may hold the key for improving available treatments and reducing morbidity and mortality for patients. Learning objectives gaining an overview of the current treatment options in primary biliary cholangitisgaining insights into the unmet clinical needs in managing primary biliary cholangitisexploring the pros and cons of PBC being a primary autoimmune diseaseexploring the pros and cons of PBC being a primary secretory disease that promotes cholestasis and subsequent immune reaction
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Pros and Cons: PBC: primary autoimmune disease or primary secretory defect? (Capital Suite 2) - Jan 4, 2022 - Abstract #EASLILC2022EASL_ILC_200;
Understanding the mechanistic basis of PBC may hold the key for improving available treatments and reducing morbidity and mortality for patients. Learning objectives gaining an overview of the current treatment options in primary biliary cholangitisgaining insights into the unmet clinical needs in managing primary biliary cholangitisexploring the pros and cons of PBC being a primary autoimmune diseaseexploring the pros and cons of PBC being a primary secretory disease that promotes cholestasis and subsequent immune reaction
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio. (Pubmed Central) - Jan 1, 2022
Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials...More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: Bile Acids Gate Dopamine Transporter Mediated Currents. (Pubmed Central) - Dec 28, 2021
This study explores the interactions of the BA, obeticholic acid (OCA), with DAT and characterizes the regulation of DAT activity via both electrophysiology and molecular modeling...Binding to that site may stabilize the inward-facing (IF) open state by preventing the re-formation of the IF-gating salt bridges, R60-D436 and R445-E428, that are required for DA transport. This study suggests that BAs may represent novel pharmacological tools to regulate DAT function, and possibly, associated behaviors.
- |||||||||| atorvastatin / Generic mfg.
Journal: Atorvastatin protects against liver and vascular damage in a model of diet induced steatohepatitis by resetting FXR and GPBAR1 signaling. (Pubmed Central) - Dec 25, 2021
Atorvastatin increased the percentage of 7α-dehydroxylase expressing bacteria in the intestine promoting the formation of deoxycholic acid and litocholic acid, two GPBAR1 agonists, along with the expression of GPBAR1-regulated genes in the white adipose tissue and colon. In conclusion, present results highlight the central role of bile acids in regulating lipid and cholesterol metabolism in response to atorvastatin and provide explanations for limited efficacy of FXR agonists in the treatment of NAFLD.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Clinical, Journal: A consensus integrated care pathway for patients with primary biliary cholangitis: a guideline-based approach to clinical care of patients. (Pubmed Central) - Dec 18, 2021
The PBC Integrated Patient Care Pathway is a best practice tool for clinicians designed to complement the EASL Clinical Practice Guidelines for the diagnosis and management of PBC patients. It gives clinicians a practical decision tree of the key steps in PBC management, thereby providing a simplified framework and an opportunity for more uniform practice that supports the safe and timely adoption of varied models of care provision to patients with PBC.
- |||||||||| bile acid cholic acid (INT-777) / Intercept
Preclinical, Journal: TGR5 Attenuated Liver Ischemia-Reperfusion Injury by Activating the Keap1-Nrf2 Signaling Pathway in Mice. (Pubmed Central) - Dec 16, 2021
We injected wild mice with a small interfering RNA of TGR5 (si-TGR5) or TGR5 agonist (INT-777) and established liver partial warm ischemia/reperfusion model...Importantly, these results were completely reversed in si-TGR5 BMDMs. In conclusion, the results indicated that TGR5 could effectively alleviated inflammation response via accelerating the activation of Keap1-Nrf2 signaling pathway during hepatic IRI, which may be meaningful in reducing related inflammatory molecules and adjusting inherent immunity.
- |||||||||| elafibranor (GFT505) / Genfit, Ocaliva (obeticholic acid) / Intercept
Journal: Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system. (Pubmed Central) - Dec 16, 2021
The effects of Obeticholic acid and Elafibranor, were evaluated in the model, as wells as the effects of dietary intervention, with all able to significantly reduce inflammatory and fibrosis markers. Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal, CME: Continuing Medical Education Questions: November 2021. (Pubmed Central) - Dec 15, 2021
Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype. Article Title: Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Preclinical, Journal: Caffeine and EGCG Alleviate High-Trans Fatty Acid and High-Carbohydrate Diet-Induced NASH in Mice: Commonality and Specificity. (Pubmed Central) - Dec 13, 2021
HFHC group mice were additionally treated with caffeine (75 mg/kg) or EGCG (100 mg/kg) for 6 weeks, using obeticholic acid (OCA,10 mg/kg) as a positive control group...The bioinformatics platform we built for caffeine and EGCG in NASH disease found that the two drugs may greatly overlap in improving the mechanism related to NASH inflammation. However, caffeine may have better potential in regulating glucose metabolism and EGCG may have better potential in regulating lipid metabolism.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Enrollment closed, Trial completion date, Trial primary completion date: COBALT: Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (clinicaltrials.gov) - Dec 7, 2021
P4, N=428, Active, not recruiting,
However, caffeine may have better potential in regulating glucose metabolism and EGCG may have better potential in regulating lipid metabolism. Recruiting --> Active, not recruiting | Trial completion date: Apr 2025 --> Dec 2021 | Trial primary completion date: Dec 2024 --> Dec 2021
- |||||||||| budesonide / Generic mfg.
Journal: Disease-modifying therapies and symptomatic management for primary biliary cholangitis. (Pubmed Central) - Dec 2, 2021
Cholestyramine is first-line therapy for pruritus, albeit with limited evidence and common side-effects...Disease-modifying and symptomatic therapies must be considered in tandem when managing patients with primary biliary cholangitis. Emerging therapies show initial promise but further randomised trials with long-term follow up are required to evaluate their efficacy as single or combination therapies.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Preclinical, Journal: Generation of a Transgenic Zebrafish Line for In Vivo Assessment of Hepatic Apoptosis. (Pubmed Central) - Nov 29, 2021
We also detected isoniazid-induced inhibition of caspase 3 activity in zebrafish that were treated with the hepatoprotectants ursodeoxycholic acid and obeticholic acid. The transgenic zebrafish that were developed in this study could be a powerful tool for identifying both hepatotoxic and hepatoprotective drugs, as well as for analyzing the effects of the genes of interest to hepatic apoptosis.
- |||||||||| rifampicin / Generic mfg.
Review, Journal: Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury. (Pubmed Central) - Nov 21, 2021
Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Clinical, Review, Journal: The risks of liver injury in COVID-19 patients and pharmacological management to reduce or prevent the damage induced. (Pubmed Central) - Nov 17, 2021
The mechanism of cellular penetration of the virus that occurs by viral entry is through the receptors of the angiotensin 2 conversion enzyme (ACE-2) host that are abundantly present in type II pneumocytes, heart cells, but also liver cholangiocytes. In this manuscript, we describe the clinical management aimed at preserving the liver or reducing the damage caused by COVID-19 and anti-COVID-19 drug treatments.
- |||||||||| budesonide / Generic mfg., bezafibrate / Generic mfg.
Clinical, Review, Journal: Definition and Management of Patients With Primary Biliary Cholangitis and an Incomplete Response to Therapy. (Pubmed Central) - Nov 12, 2021
All patients with PBC should receive initial treatment with ursodeoxycholic acid (UDCA), and odds for response are based on characteristics at baseline...Incomplete responders should be considered for second-line therapies with obeticholic acid (licensed) or fibrates (unlicensed) in addition to continued treatment with UDCA. Patients with PBC should be followed for life.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia. (Pubmed Central) - Nov 4, 2021
Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Clinical, Clinical data, Review, Journal: Zonation in NASH-a key paradigm for understanding pathophysiology and clinical outcomes. (Pubmed Central) - Nov 4, 2021
Intriguingly, morphogenic pathways known to affect zonal development and maintenance - WNT/β-Catenin, Hedgehog, HIPPO/Yap/TAZ, and Notch - have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient-specific activation of these pathways may explain the variability in clinical presentation, and the zone-specific response observed in clinical trials.
|
