Ocaliva (obeticholic acid) / Sumitomo Pharma, Intercept - LARVOL DELTA

Quick glance at 'metabolic dysfunction associated steatotic liver disease' therapeutics: Targets, trials, and trends. (PubMed, World J Gastrointest Pharmacol Ther) - "Resmetirom, a thyroid hormone receptor β (THR-β) agonist, is currently the lone agent approved for treating metabolic dysfunction-associated steatohepatitis (MASH). Off-label use of vitamin E and obeticholic acid has met with some treatment success...While metformin has largely failed to demonstrate efficacy, hepatotoxicity remains an area of concern with statin therapy...Despite encouraging advances, long-term safety, durability of response, and regulatory approvals remain key hurdles before these agents can be broadly implemented in clinical practice. This review summarizes current knowledge on the pathogenesis of MASLD/MASH and the molecular pathways that may offer therapeutic potential in managing this widespread metabolic liver disease."

Journal • Review • Cardiovascular • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Transplantation • Type 2 Diabetes Mellitus • FASN • SCD

Randomized Controlled Trial Evidence on Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis. (PubMed, Int J Hepatol) - "Ursodeoxycholic acid (UDCA) is the first-line treatment, while obeticholic acid (OCA) serves as a second-line option because of moderate UDCA nonresponsiveness and cirrhosis-related concerns. There was no significant difference between PPAR agonists and placebo for ALT level (SMD = -0.93, 95%CI = -1.94 to 0.08; p = 0.07, I2 = 95%), AST level (SMD = -0.01, 95%CI = -0.67 to 0.66; p = 0.99, I2 = 91%), and pruritus (RR = 0.77, 95%CI = 0.29 to 2.06; p = 0.60, I2 = 34%). Our study found a superior efficacy of PPAR agonists compared with placebo for change in ALP, GGT, TBil, and Tg levels, highlighting the potentially beneficial effect of PPAR agonists on liver health."

Journal • Retrospective data • Review • Dermatology • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Primary Biliary Cholangitis • Pruritus

Discovery of novel 1-(4-aminophenylacetyl)piperidine derivatives as FXR partial agonists for the potential treatment of metabolic dysfunction-associated steatohepatitis. (PubMed, Eur J Med Chem) - "V15 demonstrates an EC50 value of 0.67 ± 0.08 nM (81.3 % maximum efficacy vs obeticholic acid)...Notably, V15 exhibits good target selectivity and an acceptable safety profile. These findings suggest that the novel FXR partial agonist V15 represents a promising candidate for the treatment of MASH."

Journal • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

A critical review of natural products driven correction of bile acid dysregulation: a therapeutic strategy for nonalcoholic fatty liver disease. (PubMed, Front Pharmacol) - "While two drugs (semaglutide, resmetirom) have recently been approved for nonalcoholic steatohepatitis (NASH), their clinical utility is constrained by gastrointestinal side effects, insufficient efficacy against fibrosis, and dose-related adverse events. Similarly, obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist with antifibrotic potential, is associated with significant side effects, including severe pruritus...Future research must prioritize human-relevant models, large-scale randomized controlled trials (RCTs) with histological endpoints, and robust causal validation. By addressing these gaps, natural products targeting BA metabolism hold great promise to complement or replace existing therapies, offering safer and more effective personalized treatments for NAFLD."

Journal • Review • Dermatology • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Pruritus • Transplantation

Transcriptional and Post-Transcriptional Anticholestatic Mechanisms of Obeticholic Acid in Lipopolysaccharide-Induced Cholestasis. (PubMed, Pharmaceutics) - " OCA prevents bile-salt accumulation in LPS-induced cholestasis by enhancing Bsep expression and localization, and by mitigating inflammation. This makes OCA a promising therapeutic candidate for sepsis-induced cholestasis."

Journal • Cholestasis • Hepatology • Infectious Disease • Inflammation • Septic Shock • ABCC3

Geniposide activates the NLRP3 inflammasome pathway to induce nephrotoxicity by regulating FXR/PERK/TXNIP pathways. (PubMed, Toxicon) - "Male SD rats were orally administered geniposide (200 mg/kg), geniposide (400 mg/kg), and geniposide + obeticholic acid (OCA) (25 mg/kg) for 1 week consecutively...RT-qPCR and Western blot experiments revealed a significant upregulation of FXR mRNA and protein levels, while the mRNA and protein expression of endoplasmic reticulum stress-related proteins PERK and TXNIP, NLRP3 and Caspase-1, were downregulated. These results confirm that geniposide can induce nephrotoxicity, and the FXR/PERK/TXNIP/NLRP3 signaling pathway is involved."

Journal • IL1B • KIM1 • NLRP3 • TXNIP

Primary biliary cholangitis. Treatment options in 2025. A narrative review. (PubMed, Front Immunol) - "Ursodeoxycholic acid (UDCA) has been the treatment of choice for PBC since its approval back in 1994; however, a percentage varying from 15-40% of all patients fail to achieve biochemical response or alkaline phosphatase normalization. Obeticholic acid, though promising at first, failed to show benefit after long-term use and was retracted from the market...However, a substantial percentage of patients fail to achieve serum alkaline phosphatase and bilirubin normalization; as a result, many drugs with different mechanisms of action are in phase 2 or 3 trials. The aim of this review is to present available data regarding PBC treatment and explain the pathogenetic pathway each one targets."

Journal • Review • Cholestasis • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Study of OCA in Combination With BZF Evaluating Efficacy, Safety, and Tolerability in Participants With PBC (clinicaltrials.gov) - P2 | N=75 | Terminated | Sponsor: Intercept Pharmaceuticals | Active, not recruiting ➔ Terminated; Intercept made a business decision to terminate the study based on FDA's request for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies under US IND involving OCA.

Trial termination • Hepatology • Immunology • Primary Biliary Cholangitis

Letter on 'Non-Response to Obeticholic Acid Is Associated With Heightened Risks of Developing Clinical Events in Primary Biliary Cholangitis'. (PubMed, Aliment Pharmacol Ther) - No abstract available

Journal • Hepatology • Immunology • Primary Biliary Cholangitis

Testing Obeticholic Acid for Familial Adenomatous Polyposis (clinicaltrials.gov) - P2 | N=80 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2026 ➔ Feb 2029 | Trial primary completion date: Jan 2026 ➔ Jan 2029

Trial completion date • Trial primary completion date • Colorectal Cancer • Genetic Disorders • Oncology • Small Intestinal Carcinoma • Solid Tumor • APC

UDCA Treatment Response in Primary Biliary Cholangitis in the United States (ISPOR-EU 2025) - "Many patients have inadequate response to ursodeoxycholic acid (UDCA), the recommended first-line treatment for PBC...Patients prescribed obeticholic acid or fibrates at baseline were excluded... Although 69% of patients with PBC met the composite response endpoint, the majority did not achieve ALP normalization. This highlights the need for effective second-line treatment options. Several demographic and clinical predictors of response emerged suggesting opportunities to tailor therapies to specific patient subgroups."

Autoimmune Hepatitis • Fibrosis • Hepatology • Immunology • Inflammation • Primary Biliary Cholangitis

Humanistic and Economic Burden of Primary Biliary Cholangitis: A Systematic Review of Health-Related Quality of Life Healthcare Resource Utilization and Associated Cost (ISPOR-EU 2025) - "Second-line treatment with obeticholic acid (OCA)/fibrates ± ursodeoxycholic acid (UDCA) incurred the highest total direct cost, followed by untreated and first-line (UDCA). PBC significantly impairs HRQoL and imposes a substantial economic burden due to high HCRU and treatment costs. This review underscores the critical need for timely and effective therapies that prioritize disease modification, symptom management, and overall patient well-being."

Clinical • HEOR • Review • Dermatology • Fatigue • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Beyond Ursodeoxycholic Acid: A Comprehensive Review of Second-Line Agents in Primary Biliary Cholangitis. (PubMed, Cureus) - "However, the therapeutic landscape is evolving with the recent approval of elafibranor and seladelpar, offering new hope for patients and clinicians alike...Special attention is given to the clinical implications of their approval and accessibility within NHS pathways. In addition to disease-modifying therapies, adjunctive strategies for symptom control, particularly for pruritus and fatigue, are also discussed, along with a brief overview of future therapeutic directions. By summarising the expanding treatment arsenal, this review aims to support evidence-informed decision-making and promote timely specialist referral in patients with suboptimal response to UDCA."

Journal • Review • Cholestasis • Dermatology • Fatigue • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

FXR-targeted drug discovery: Recent advances and therapeutic perspectives. (PubMed, Eur J Med Chem) - "In 2016, obeticholic acid (OCA) received approval from FDA for marketing...Notable candidates include Tropifexor (for non-alcoholic steatohepatitis, NASH), Cilofexor (for PBC), and Nidufexor (for diabetic nephropathy). This review delineates the structural features and biological functions of FXR, analyzes molecular mechanisms underpinning its signal transduction pathways and disease pathogenesis, and highlights molecular design strategies and structure-activity relationship (SAR) advancements in FXR agonists. These insights aim to provide a theoretical foundation for rationally designing novel, potent FXR agonists."

Journal • Diabetic Nephropathy • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Primary Biliary Cholangitis • Renal Disease

Representation of Lean Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease in Randomized Controlled Trials: A Systematic Review of Methodology (ACG 2025) - "Retrospective studies, studies using herbal therapies or obeticholic acid, and studies lacking liver-related outcomes were excluded...Only four trials explicitly included a lean subgroup; of these, just one trial reported BMI-stratified outcomes, demonstrating hepatic fat reduction with empagliflozin pharmacotherapy in non-diabetic lean patients. From 780 records identified, 738 unique abstracts were screened after de-duplication. Of these, 141 full-text articles were reviewed, and 71 RCTs were included in the final analysis. Our results showed that BMI-based inclusion or exclusion criteria were applied in 34 trials (48%)."

Clinical • Review • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

Real-World Clinical Outcomes of Obeticholic Acid Plus Ursodeoxycholic Acid versus Ursodeoxycholic Acid Alone in Non-Cirrhotic Patients With Primary Biliary Cholangitis (ACG 2025) - "Patients receiving OCA+UDCA had a significantly higher incidence of pruritus compared to those on UDCA monotherapy (8.4% vs. 4.2%; RR 2.00; 95% CI, 1.29–3.11; p=0.002). No significant difference was observed in the incidence of jaundice between groups (1.5% each; RR 1.00; 95% CI, 0.42–2.39; p=1.000)."

Clinical • Clinical data • Real-world • Real-world evidence • Dermatology • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Primary Biliary Cholangitis • Pruritus

PBC Without Biochemical Remission. What Is the Role of Obeticholic Acid? (ACG 2025) - "Ursodeoxycholic acid (URSO) is the first line agent for PBC, but some require another agent to achieve biochemical remission. 286 patients with PBC were identified of which 19 are on OCA therapy and 9 recently discontinued due to intolerance or unclear benefit. The average duration of therapy was 1,375 days or 3.7 years with a range of 279-2655 days. 73.7% (n=15) are biochemical non-responders."

Clinical • Cholestasis • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis

Primary Biliary Cholangitis: Second-Line Treatment and Outcomes at a Safety Net vs Tertiary Care Hospital Systems (ACG 2025) - "Patients at the TCH who met criteria for second line therapy were more likely to receive second line therapy with obeticholic acid or fenofibrate (14/19 vs. 10/40, p = 0.02). Patients at the SNH were of similar age to those at TCH (53.0 vs 54.6 years) but had significantly higher rates of uninsured or Medicaid status (63% vs. 8.3%; p < 0.001), were predominantly Hispanic (78.7% vs. 15.0%, p < 0.001) and had AMA-negative disease diagnosed by biopsy more frequently (32.7% vs."

Clinical • Fibrosis • Hepatology • Immunology • Liver Failure • Primary Biliary Cholangitis

Safety and Efficacy of Obeticholic Acid in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis (ACG 2025) - "While Ursodeoxycholic acid (UDCA) has shown to prevent progression, nearly 40% patients do not show complete biochemical response to UDCA. The study included a total of 6 different groups, where 668 subjects received OCA therapy and 475 subjects received standard treatment. The Biochemical response rate was significantly higher in the OCA group in comparison to the control group.(OR = 3.75(1.47; 9.58) , I^2 = 93% , p < 0.01). The risk of adverse events was statistically insignificant between the two groups.(RR = 2.42(0.77; 7.59) , I^2 = 58% , p = 0.07). The conducted analysis highlights the clinical efficacy of Obeticholic acid in effective management of Primary Biliary Cholangitis."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Liver Failure • Primary Biliary Cholangitis

Efficacy and Safety of Seladelpar in Patients With Primary Biliary Cholangitis Previously Treated With Fibrates or Obeticholic Acid (ACG 2025) - P3 | "Introduction: Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in patients (pts) with an inadequate response to UDCA or as monotherapy in pts unable to tolerate UDCA. Among pts who continued into ASSURE from RESPONSE (n = 158), 16 continuous seladelpar and 11 crossover pts reported prior use of fibrates/OCA (total, n = 27; 17%); 88 continuous seladelpar and 43 crossover pts reported no prior use of fibrates/OCA (total, n = 131; 83%). At month 18, among continuous seladelpar pts, 9/15 (60%) pts with prior fibrate/OCA use achieved a CBR vs 54/87 (62%) pts without prior fibrate/OCA use. Among crossover pts, 7/11 (64%) pts with prior fibrate/OCA use vs 32/41 (78%) pts without prior fibrate/OCA use achieved a CBR at month 6 of ASSURE."

Clinical • Hepatology • Immunology • Primary Biliary Cholangitis

Limited Approvals in MASLD Highlight the Need to Reevaluate FDA Guidance for Outcome Measures (ACG 2025) - "SGLT-2 inhibitor, Ipragliflozin demonstrated significant improvement in fibrosis (OR 7; 95% CI 1.77-27.68), however it's effect on steatohepatitis was not reported. While GLP-1 receptor agonist (GLP-1 RA) Liraglutide had significant impact of steatohepatitis resolution (OR 6.43; 95% CI 1.20-34.41) in a phase 2 trial without a follow up phase 3 study...Obeticholic acid did show improvement in fibrosis (OR 2.22; 95% CI 1.44-3.42), but did not receive FDA approval due to its risk-benefit profile. Resmetirom is currently the only FDA-approved therapy for MASLD... Of the 464 RCTs identified, only 63 were assessing pharmacotherapies. Despite these drugs demonstrating meaningful improvement through non-invasive assessments such as FibroScan and MRI-PDFF, over 75% of these studies were not eligible for FDA approval pathways, given the current regulatory requirement of biopsy-based endpoints. Only 10 of the 63 studies were evaluating liver biopsy based on steatohepatitis..."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Innate immunity of bile and cholangiocytes in primary biliary cholangitis. (PubMed, Front Immunol) - "Current clinical management with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) primarily addresses cholestasis...Targeted therapeutic strategies addressing innate immune pathways-exemplified by RIPK2 (Receptor Interacting Serine/Threonine Kinase 2) inhibition, IL-1 blockade(Canakinumab), and T cell immunoglobulin mucin domain-containing protein 3 (TIM-3) modulation-alongside cell-based interventions such as mesenchymal stem cell therapy, demonstrate considerable therapeutic potential...Achieving therapeutic precision requires deeper elucidation of the gut-biliary-immune axis, trained immunity mechanisms, and cholangiocyte senescence, paving the way for targeted interventions in PBC. Establishing a comprehensive treatment burden assessment system is imperative to facilitate the transition from investigational platforms to clinical care."

Journal • Review • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Primary Biliary Cholangitis • HAVCR2 • IFNG • IL17A • RIPK2

Study to Assess Efficacy, Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Obeticholic Acid (OCA) Compared to Placebo in Pediatric Participants With Biliary Atresia, Post-hepatoportoenterostomy (clinicaltrials.gov) - P2/3 | N=28 | Terminated | Sponsor: Intercept Pharmaceuticals | N=144 ➔ 28 | Active, not recruiting ➔ Terminated; Intercept made a business decision to terminate the study based on FDA's request for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies under US IND involving OCA.

Enrollment change • Trial termination • Hepatology • Pediatrics

Treatment Persistence, Normal Alkaline Phosphatase and Clinical Outcomes in Primary Biliary Cholangitis. (PubMed, Aliment Pharmacol Ther) - "Treatment persistence is crucial in PBC as it is associated with normal ALP and significant improvement in clinical outcomes. Novel strategies and therapies are needed to enhance persistence and improve clinical benefits among individuals with PBC."

Clinical data • Journal • Cardiovascular • Dermatology • Fatigue • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Infectious Disease • Inflammatory Arthritis • Liver Cirrhosis • Lupus • Pain • Portal Hypertension • Primary Biliary Cholangitis • Pruritus • Systemic Lupus Erythematosus • Transplantation • Urology

Benzoxazole Derivatives as Potent FXR and PPARα Dual Agonists With Anti-Fibrotic and Metabolic Regulatory Effects. (PubMed, MedComm (2020)) - "In a thioacetamide-induced liver fibrosis model, MHY5396 had an anti-fibrotic effect comparable to obeticholic acid, a potent FXR agonist...Pharmacokinetic studies showed that orally administered MHY5396 was well absorbed (F = 98.6%) and primarily metabolized by hepatic CYP1A2 with negligible urinary excretion. Overall, MHY5396, with dual FXR and PPARα agonist activity, exhibited significant anti-fibrotic and metabolic regulatory properties in liver and kidney fibrosis models, presenting a novel therapeutic potential for fibrotic diseases."

Journal • Fibrosis • Immunology • Inflammation • Liver Cirrhosis • CYP1A2 • PPARA • TGFB1