Alagille syndrome: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Alagille syndrome is a multisystem autosomal dominant disorder caused by JAG1 or NOTCH2 gene mutations, disrupting Notch signaling [2][10]. It primarily manifests as cholestasis due to bile duct paucity, with characteristic facial features, cardiac anomalies (e.g., pulmonic stenosis), and ocular/skeletal involvement [1][5][7]. Disease severity varies widely, ranging from asymptomatic carriers to life-threatening liver/cardiac complications [4][11].

Population

Prevalence: ~1:30,000–50,000 live births [11][19]
30-50% inherit mutations; remaining cases are de novo [2][11]
Diagnosed via clinical criteria (3/5 features: cholestasis, cardiac defects, butterfly vertebrae, embryotoxon, facial dysmorphism) ± genetic testing [5][18]

Burden

11-35% mortality over decades, primarily from cardiac/vascular complications [4][15]
66-88% experience debilitating pruritus; 30-40% develop xanthomas [10][13]
Impaired HRQoL scores (PedsQL 4.0: 57.1 vs 83.3 in controls) [13], frequent hospitalizations, and high transplant-related costs [9][13]

Therapies

Medical: IBAT inhibitors (maralixibat/odevixibat) for pruritus [8][20], ursodiol, rifampin, antihistamines [12][16], and fat-soluble vitamin supplementation [3][14]
Surgical: Partial external biliary diversion for refractory pruritus; liver transplantation in 15-47% by adolescence [3][16]
Supportive: High-calorie diets, MCT-rich formulas, gastrostomy feeding for growth failure [3][16]

Categories: rare abdominal surgical diseases, rare cardiac malformations, rare developmental anomalies during embryogenesis, rare genetic diseases, rare hepatic diseases, rare neoplastic diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders

Research Papers

315 drug discovery papers related to Alagille syndrome, with 5 first-in-class and 4 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:

2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.

The increasing availability and decreasing costs of DNA sequencing have resulted in the re-grouping of rare, severe paediatric cases of progressive familial intrahepatic cholestasis (PFIC) with more frequent, later-onset cases of cholestasis (eg, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis, low phospholipid-associated cholelithiasis) under the umbrella of genetic cholestasis. The common denominator is the presence of functional variants in the PFIC-associated genes, predominantly in ABCB4, ABCB11 and ATP8B1, which cause PFIC types 1-3. Several other congenital diseases such as Alagille syndrome and alpha1-antitrypsin deficiency comprise cholestatic pruritus as frequent symptoms.With the availability of intestinal bile acid transporter inhibitors (IBATi) as new and efficacious therapeutics for pruritus, the most debilitating symptom of PFIC, it is essential to envision their usefulness for patients with later-onset cholestatic liver disease suffering from pruritus.In this review, we summarise published studies on the genetic makeup of patients with paediatric, juvenile and adult-onset cholestasis, and discuss their findings with respect to genotype-specific treatment with IBATi, ursodeoxycholic acid, or alternative drugs. The aim is to provide an overview of the genetic variants likely to be encountered in future sequencing investigations of patients with cholestatic liver diseases, and how to translate this genetic information into personalised treatment recommendations.

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2026-05-04 | From supportive to targeted treatment strategies: the changing landscape of therapeutics in Alagille syndrome

1. Alagille syndrome (ALGS) is an autosomal dominant developmental disorder characterized by highly variable, multisystem involvement and caused by pathogenic variants in the genes Jagged1 (JAG1) a...

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2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.

Open article ↗

2026-05-04 | From supportive to targeted treatment strategies: the changing landscape of therapeutics in Alagille syndrome

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Drug Discovery Landscape

6 orphan drug designations for Alagille syndrome, including 3 approved therapies.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
27mer antisense oligonucleotide with methoxyethyl, 2'-O-methyl, and phosphorothioate modifications	oligonucleotides	FDA	2024-10-24	—	Arnatar Therapeutics, Inc.
odevixibat [Bylvay]	small molecules	FDA	2018-10-15	2023-06-13	Ipsen Biopharmaceuticals, Inc.
(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-1-azoniabicyclo[2.2.2]octane chloride [Livmarli]	small molecules	EMA	2013-12-18	2022-12-12	Mirum Pharmaceuticals International B.V.
maralixibat [Livmarli]	small molecules	FDA	2013-09-04	2021-09-29	Mirum Pharmaceuticals, Inc.
Odevixibat sesquihydrate [Bylvay]	small molecules	EMA	2012-08-09	—	Albireo AB
Buffered Ursodeoxycholic Acid	small molecules	FDA	2004-09-03	—	Digestive Care, Inc.

Alagille syndrome

Alagille syndrome

Alagille syndrome

Overview

Population

Burden

Therapies

Categories: rare abdominal surgical diseases, rare cardiac malformations, rare developmental anomalies during embryogenesis, rare genetic diseases, rare hepatic diseases, rare neoplastic diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders

Research Papers

2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.

2026-05-04 | From supportive to targeted treatment strategies: the changing landscape of therapeutics in Alagille syndrome

2026-06-18 | Use of genetic analysis in adult cholestatic liver disease: lessons from progressive paediatric syndromes and cohort studies.

2026-05-04 | From supportive to targeted treatment strategies: the changing landscape of therapeutics in Alagille syndrome

Drug Discovery Landscape

Updated: Jul 30, 2026