Primary sclerosing cholangitis: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Primary Sclerosing Cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease characterized by progressive inflammation, fibrosis, and stricturing of intra- and extrahepatic bile ducts. It is strongly associated with inflammatory bowel disease (IBD) in 70–80% of cases [1][6][12]. Clinical manifestations include fatigue, pruritus, jaundice, and recurrent cholangitis, with late-stage complications such as cirrhosis, portal hypertension, and hepatobiliary cancers (e.g., cholangiocarcinoma in 10–15% of patients) [1][12][20]. Diagnosis relies on cholangiography (MRCP/ERCP) and exclusion of secondary causes [1][6]. Liver transplantation is the only curative option for advanced disease, though recurrence occurs in 25–30% of cases [12][16].

Population

Predominantly affects males (2:1 male-to-female ratio), with a median age of diagnosis at 40 years [1][12].
Incidence: 0.87 per 100,000 annually; prevalence: 13.5 per 100,000 [2][19].
64–80% have comorbid IBD (ulcerative colitis > Crohn’s disease) [7][12].

Burden

Survival: Median transplant-free survival 21 years; 50% mortality at 21 years post-diagnosis [9][12].
Cancer risk: 10–15% lifetime risk of cholangiocarcinoma; 10-fold increased risk of colorectal cancer in IBD patients [12][20].
Quality of life: 48% loss of quality-adjusted life years (QALYs) >25 years post-diagnosis, 25% work productivity loss [9].
Healthcare utilization: Annual costs ~€12,169/patient, with 12.4 hospital contact days/year [9][10].

Therapies

Symptom management: Pruritus treated with cholestyramine, rifampicin, or opioid antagonists; antibiotics for recurrent cholangitis [3][8][13].
Endoscopic intervention: Balloon dilation/stenting for dominant strictures [3][13].
Liver transplantation: Indicated for decompensated cirrhosis or cholangiocarcinoma; 10-year survival post-transplant >80% [4][9][16].
No disease-modifying therapies exist, though high-dose ursodeoxycholic acid (13–15 mg/kg/day) is commonly used [3][5].

Categories: rare hepatic diseases, rare transplant-related disorders

Research Papers

1,443 drug discovery papers about Primary sclerosing cholangitis, with 2 first-in-class and 32 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:

2026-06-29 | Successful Treatment of Refractory Pruritus in Primary Sclerosing Cholangitis with Upadacitinib: A Case Report.

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that is often complicated by severe pruritus, which can profoundly impair quality of life. In select cases, intractable pruritus is an independent indication for liver transplantation (LT) even in the absence of advanced liver disease, recurrent cholangitis, or malignancy. Conventional pharmacological and endoscopic therapies frequently provide only partial or transient relief, highlighting the need for mechanism-based treatments. We report the case of a 32-year-old man with long-standing PSC and Crohn's disease (CD) who developed severe treatment-refractory pruritus despite multiple conventional pharmacologic therapies and endoscopic biliary interventions. In the absence of advanced liver disease or malignancy, he underwent LT evaluation primarily due to debilitating pruritus significantly impairing quality of life, with secondary consideration given to medically and endoscopically challenging but manageable recurrent dominant common bile duct stricture and episodes of acute cholangitis. Upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, was initiated for a CD flare, after which pruritus completely resolved within 48-72 h. Maintenance therapy with upadacitinib 30 mg daily has sustained symptom-free status for over 27 months, markedly improving quality of life and allowing the patient to remain inactive on the liver transplant waitlist. This case demonstrates the rapid and durable resolution of PSC-associated pruritus with JAK1 inhibition. Effective symptom control allowed deferral of LT driven primarily by quality-of-life impairment, with the patient remaining inactive on the waitlist. To our knowledge, this is the first reported case of successful treatment of PSC-associated pruritus with upadacitinib, supporting further investigation of JAK1 inhibition as a potential therapeutic strategy for cholestatic pruritus.

Open article ↗

2026-06-26 | Multi-Omics Integrative Analysis Identifies the NK Cell-STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis.

Primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) exhibit a striking clinical comorbidity, with 60-80% of PSC patients concurrently harboring UC, yet the shared immunogenetic mechanisms remain poorly understood. Here, we constructed a multi-omics integrative framework to systematically dissect the cellular and molecular basis of this comorbidity. GWAS meta-analyses were performed for each disease, followed by tissue-level enrichment assessment using QTLEnrich, MAGMA, and gsMap spatial mapping. Single-cell transcriptomic atlases were constructed, and cell-type prioritization was conducted using four complementary methods. Core genes were identified through cross-validation of five algorithms, with subsequent genomic fine-mapping via FUMA and GCTA-COJO. Tissue-level analyses consistently identified the intestine and immune-related tissues as commonly affected. Multi-dimensional evidence integration prioritized natural killer (NK) cells as the core effector cell type for both diseases, supported principally by CELLECT (Cell-type Expression-specific Integration for Complex Traits) heritability enrichment and single-cell differential analysis. Convergence of five gene-level algorithms pinpointed STAT3 as the sole high-confidence comorbidity gene, broadly expressed across immune cell populations and exhibiting tissue-differential alternative splicing. Colocalization identified a high-risk variant (rs3736161) within the STAT3 locus, with conditional analysis revealing 35 additional independent signals. These findings identify the NK cell-STAT3 axis as a central immunogenetic hub connecting PSC and UC, offering potential therapeutic targets for comorbidity management.

Open article ↗

2026-06-25 | Annexin A2 as a therapeutic target of Artemisiae Scopariae Herba-derived quercetin in preventing malignant progression from primary sclerosing cholangitis to cholangiocarcinoma: An integrative study.

Artemisiae Scopariae Herba (ASH) is traditionally used to treat cholestatic liver diseases and exhibits anti-tumour potential. Cholangiocarcinoma (CCA) and its major risk factor, primary sclerosing cholangitis (PSC), lack effective therapies. In this study, we aimed to elucidate the bioactive constituents and underlying protective mechanisms of ASH in preventing malignant progression from PSC to CCA. We identified the active constituents of ASH and their targets using multiple databases and mass spectrometry. Integrative transcriptomic analysis of public datasets determined the therapeutic targets. Machine learning and molecular docking predicted key targets, while surface plasmon resonance experimentally confirmed the primary drug-target interaction. Subsequent clinical sample analysis validated these targets. Finally, we assessed the in vitro effects of quercetin on CCA cells and utilised single-cell transcriptomics to characterise target expression within the disease microenvironment. Quercetin emerged as the principal bioactive constituent of ASH, with annexin A2 (ANXA2) as its key target. ANXA2 was overexpressed in CCA and PSC, which correlated with poor patient prognosis. In vitro, quercetin suppressed CCA cell malignant phenotypes and downregulated ANXA2 expression. Single-cell analysis revealed that epithelial cells, functioning as critical communication hubs, primarily overexpressed ANXA2. Functional enrichment analysis implicated pathways regulating the actin cytoskeleton and mediating bacterial infection responses. Quercetin likely exerts its therapeutic effects by targeting ANXA2 and modulating cholangiocyte pathogenicity. These findings highlight ANXA2 as a promising therapeutic target for treating advanced CCA and halting PSC-driven carcinogenesis.

Open article ↗

2026-06-29 | Successful Treatment of Refractory Pruritus in Primary Sclerosing Cholangitis with Upadacitinib: A Case Report.

Open article ↗

2026-06-26 | Multi-Omics Integrative Analysis Identifies the NK Cell-STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis.

Open article ↗

2026-06-25 | Annexin A2 as a therapeutic target of Artemisiae Scopariae Herba-derived quercetin in preventing malignant progression from primary sclerosing cholangitis to cholangiocarcinoma: An integrative study.

Open article ↗

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Drug Discovery Landscape

37 orphan drug designations for Primary sclerosing cholangitis.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
Leuconostoc citreum, strain G511, Live	other	EMA	2025-11-21	—	Harvest Integrated Research Organization Ireland Limited
Elafibranor	small molecules	EMA	2025-07-18	—	Ipsen Pharma
elafibranor	small molecules	FDA	2025-07-16	—	IPSEN Bioscience Inc.
Beta-lapachone	small molecules	EMA	2025-06-20	—	Hungarotrial Zrt.
Volixibat potassium	small molecules	EMA	2025-02-26	—	Mirum Pharmaceuticals International B.V.
small molecule inhibitor of hyaluronan synthesis	small molecules	FDA	2024-04-09	—	Halo Biosciences, Inc.
Aldafermin	proteins	FDA	2023-12-21	—	NGM Biopharmaceuticals Inc.
Live biotherapeutic product consisting of a single bacterial strain (Leuconostoc citreum [L. citreum])	cell therapies	FDA	2022-12-01	—	LISCure Biosciences Inc.
3-([3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1Lambda6,2,5-benzothiadiazepin-8-yl]oxy)propanoic acid	small molecules	FDA	2022-11-15	—	Albireo AB
Bezafibrate	small molecules	EMA	2022-08-10	—	Amsterdam UMC
Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu- Gly-Pro-Pro-Pro-Ala-Leu-Ala-Leu-Ala-NH2	peptides	FDA	2022-05-24	—	Sterotherapeutics, LLC
Bexotegrast	small molecules	EMA	2022-04-13	—	Pharma Gateway AB
Beta-Lapachone	small molecules	FDA	2022-03-28	—	Curome Biosciences Co., Ltd.
Chimeric peptide of human glucagon-like peptide-1, glucagon and gastric inhibitory polypeptide analogues linked to a human immunoglobulin Fc fragment	proteins	EMA	2021-12-10	—	JVM Europe B.V.
3-(4-((3-endo)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one	small molecules	FDA	2021-09-13	—	Cascade Pharmaceuticals, Inc
Norucholic acid	small molecules	FDA	2021-06-24	—	Dr. Falk Pharma GmbH
Humanised IgG1 monoclonal antibody against human eotaxin-2	antibodies	EMA	2020-08-21	—	FGK Representative Service GmbH
Glucagon-like peptide-1/Glucagon/Gastric inhibitory polypeptide triple agonist linked to human IgG4 Fc fragment	peptides	FDA	2020-03-04	—	Hanmi Pharmaceutical Company, Ltd.
Cilofexor trometamol	small molecules	EMA	2019-04-01	—	Gilead Sciences Ireland Unlimited Company
small molecule inhibitor of integrins avEszett6 and avEszett1	small molecules	FDA	2018-11-19	—	Pliant Therapeutics, Inc.
2-[3-(2-chloro-4-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}phenyl)-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid¿2-amino-2-(hydroxymethyl)propane-1,3-diol (1/1)	small molecules	FDA	2018-10-25	—	Gilead Sciences, Inc.
Monoclonal antibody targeting CCL24	antibodies	FDA	2018-10-11	—	ChemomAb, Ltd.
(S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid	small molecules	EMA	2017-10-16	—	Pharma Gateway AB
5-cholesten-3ß, 25-diol 3-sulfate sodium salt (25HC3S)	small molecules	FDA	2017-07-06	—	DURECT Corporation
(S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid	small molecules	FDA	2017-06-21	—	Conatus Pharmaceuticals
Cotsiranib	RNAs	FDA	2017-06-15	—	Sirnaomics, Inc.
berberine ursodeoxycholate	small molecules	FDA	2016-08-29	—	HighTide Therapeutics (Hong Kong) Limited
recombinant, fully-human, IgG4 immunoglobulin with antigen-binding specificity for human vascular adhesion protein-1 (VAP-1)	antibodies	FDA	2016-08-25	—	Acorda Therapeutics, Inc.
Aldafermin	proteins	EMA	2015-12-14	—	Propharma Group The Netherlands B.V.
Recombinant human monoclonal antibody binding to vascular adhesion protein-1	antibodies	EMA	2015-03-19	—	Biotie Therapies Oy
simtuzumab	antibodies	FDA	2015-01-05	—	Gilead Sciences, Inc.
docosahexaenoic acid, DHA	small molecules	FDA	2014-12-17	—	Micelle BioPharma, Inc.
Norursodeoxycholic acid	small molecules	EMA	2014-07-04	—	Dr Falk Pharma GmbH
Obeticholic acid [Ocaliva]	small molecules	EMA	2014-01-16	—	[INACTIVE] Intercept Pharma International Limited
Maralixibat chloride	small molecules	EMA	2013-12-18	—	Mirum Pharmaceuticals International B.V.
(4R,5R)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-l-azoniabicyclo[2.2.2]octane Chloride	small molecules	FDA	2013-09-04	—	Mirum Pharmaceuticals, Inc.
6-alpha-ethylchenodeoxycholic acid	small molecules	FDA	2008-04-09	—	Intercept Pharmaceuticals, Inc.

Primary sclerosing cholangitis

Primary sclerosing cholangitis

Primary sclerosing cholangitis

Overview

Population

Burden

Therapies

Categories: rare hepatic diseases, rare transplant-related disorders

Research Papers

2026-06-29 | Successful Treatment of Refractory Pruritus in Primary Sclerosing Cholangitis with Upadacitinib: A Case Report.

2026-06-26 | Multi-Omics Integrative Analysis Identifies the NK Cell-STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis.

2026-06-25 | Annexin A2 as a therapeutic target of Artemisiae Scopariae Herba-derived quercetin in preventing malignant progression from primary sclerosing cholangitis to cholangiocarcinoma: An integrative study.

2026-06-29 | Successful Treatment of Refractory Pruritus in Primary Sclerosing Cholangitis with Upadacitinib: A Case Report.

2026-06-26 | Multi-Omics Integrative Analysis Identifies the NK Cell-STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis.

2026-06-25 | Annexin A2 as a therapeutic target of Artemisiae Scopariae Herba-derived quercetin in preventing malignant progression from primary sclerosing cholangitis to cholangiocarcinoma: An integrative study.

Drug Discovery Landscape

Updated: Aug 22, 2026