Abstract
Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver‐damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.
Keywords: bile acids and salts, cholestasis, paediatrics, pruritus, sodium‐bile acid cotransporter
Abbreviations
- ABCB11
ATP‐binding cassette, sub‐family B, member 11 protein
- ALGS
Alagille syndrome
- ATP8B1
ATPase phospholipid transporting 8B1 protein
- BSEP
bile salt export pump
- C4
7α‐hydroxy‐4‐cholesten‐3‐one
- ChiLDReN
Childhood Liver Disease Research Network
- FGF19
fibroblast growth factor
- FXR
farnesoid X receptor
- GALA
Global ALagille Alliance
- IBAT
ileal bile acid transporter
- JAGGED1
gene encoding a ligand of the Notch signalling pathway
- NAPPED
NAtural course and Prognosis of PFIC and Effect of biliary Diversion
- NASH
nonalcoholic steatohepatitis
- norUDCA
norursodeoxycholic acid
- PBC
primary biliary cholangitis
- PEBD
partial external biliary diversion
- PFIC
progressive familial intrahepatic cholestasis
- PSC
primary sclerosing cholangitis
- SBD
surgical biliary diversion
- UDCA
ursodeoxycholic acid
Key points.
Patients with the cholestatic liver diseases Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) have high disease burden and unmet medical needs.
Currently, the only truly effective treatments for ALGS and PFIC are surgeries that disrupt the enterohepatic circulation of bile acids and liver transplantation.
A number of potential treatment alternatives are in development to target mechanisms of cholestatic liver disease noninvasively, including ileal bile acid transport (IBAT) inhibitors.
Phase 2 and 3 trial data suggest that IBAT inhibitors, which act by interrupting the enterohepatic circulation, may be safe and efficacious treatment options for ALGS and PFIC.
1. INTRODUCTION
Adequate enterohepatic circulation is crucial for homeostatic maintenance of the bile acid pool in the body. This process starts with bile acid synthesis in hepatocytes and their subsequent biliary secretion, primarily mediated by the bile salt export pump (BSEP) at the apical (canalicular) membrane. Bile salts then move through bile ducts as constituents of bile to the gallbladder for storage and, later, for release into the small intestine to aid in lipid digestion and absorption. Per cycle, up to 95% of bile acids are reabsorbed from the terminal ileal lumen by the ileal bile acid transporter (IBAT; also known as the apical sodium‐dependent bile acid transporter) for return to the liver through the portal veins (Figure 1A). 1 Bile acid export from hepatocytes may occur at the basolateral membrane, which directs bile acids into systemic circulation. Under physiologic conditions, this export pathway is minimal; however, this may be enhanced in certain situations as a hepatoprotective mechanism, such as during cholestasis. 2 , 3 Bile acids that are not recovered from the intestine are lost in faeces (~5%) and, under steady‐state conditions, are replaced by hepatic de novo synthesis.
Figure 1.
Role of IBAT, bile acids and enterohepatic circulation in homeostasis and disease. A, Bile acids, synthesized in and secreted from the liver, travel to the small intestine where they aid in digestion and absorption of nutrients. Bile acids are reabsorbed from the terminal ileum by IBAT (95%) and return to the liver through the portal veins (indicated by the red line). This cycle is known as enterohepatic circulation. Bile acids not recovered in this process are replaced by nascent synthesis (5%), which is governed by inhibitory feedback from FGF19. The synthesis intermediate C4 is frequently used as a readout of bile acid synthesis. High bile acid levels in the ileum prompt FGF19 signalling, which suppresses further bile acid production (indicated by a decrease in C4 levels). Typical bile acid concentrations in liver cells, the biliary and intestinal tracts and the portal circulation are given in milli‐ or micromolar quantities, as applicable. 1 B, Pharmacologic inhibition of IBAT (the ileal bile acid transporter), a novel strategy being explored as treatment for Alagille syndrome and progressive familial intrahepatic cholestasis, prevents the recirculation of bile acids, shunting them away from the liver and towards faecal excretion instead, which is expected to reduce the overall size of the bile acid pool. C4 (7α‐hydroxy‐4‐cholesten‐3‐one), bile acid precursor; FGF19, fibroblast growth factor 19 3
The bile acid pool size is regulated by feedback loops: the nuclear sensor farnesoid X receptor (FXR) responds to bile acid concentrations at various points along the enterohepatic circulation by signalling to repress the synthesis of additional bile acids. For example, after bile acid reuptake from the intestinal lumen at the level of the terminal ileum, the bile acids activate FXR and thereby FXR‐responsive genes like fibroblast growth factor 19 (FGF19); once expressed, FGF19 protein is secreted and relays information from enterocytes to the liver, such that enzymes involved in the synthesis of bile acids (eg cholesterol 7 alpha‐hydroxylase) are subsequently repressed. Bile acid synthesis is commonly quantified by the serum levels of the intermediate synthesis product C4 (7α‐hydroxy‐4‐cholesten‐3‐one), which tends to negatively correlate with FGF19 levels (ie bile acid accumulation drives FGF19 formation, resulting in lower C4 levels [and bile acid synthesis; Figure 1A] 1 ; the converse is also true: diminished intestinal FXR activation by bile acids decreases FGF19 production, leading to enhanced bile acid synthesis and higher C4 levels). 4 , 5
Cholestasis is defined as the impaired formation or flow of bile in the hepatobiliary system and may be intrahepatic (involving hepatocytes, bile canaliculi or intrahepatic bile ducts) or extrahepatic (involving the bile ducts outside the liver or the gallbladder). 6 , 7 , 8 In cholestasis, which can present with features of jaundice or pruritus, the accumulation of bile acids may damage liver cells such that fibrotic and inflammatory pathways are activated that lead to liver injury. 1 , 2 , 6 Common cholestatic liver diseases include Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia in children and primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) in adults.
This review focuses on ALGS and PFIC, which are inherited and severe intrahepatic cholestatic liver diseases in children. This review will explore the therapeutic potential of interrupting the enterohepatic circulation via pharmacologic blockade of IBAT and the associated implications for treating cholestatic liver diseases and other disorders.
2. OVERVIEW OF ALGS AND PFIC
ALGS and PFIC are genetic diseases that can present in paediatric patients as severe cholestasis and result from intrahepatic perturbations. 6 , 7 ALGS can be characterized by a reduction of intrahepatic bile ducts (in association with abnormalities in a number of non‐liver organ systems such as heart defects, dysmorphic facial features, and vascular, vertebral and ocular anomalies), 9 , 10 with clinical severity that ranges from biochemical liver abnormalities only to end‐stage liver disease. 10 , 11 PFIC represents a group of disorders (with subtypes grouped based on the underlying genetic deficiency; eg ATP8B1‐deficient PFIC, ABCB11‐deficient PFIC) in which disruption of bile homeostasis can eventually lead to cholestasis, cirrhosis, liver failure and death. 12 , 13 , 14 Although distinctly different in many aspects, patients with ALGS and PFIC can share common clinical traits such as cholestasis, pruritus and an eventual need for liver transplantation. 15 , 16 Table 1 provides additional details on the incidence, genetic basis, proposed mechanisms of disease, clinical presentation and disease progression of ALGS and PFIC. 7 , 9 , 10 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28
Table 1.
ALGS and PFIC: disease characteristics and pathophysiology
ALGS | PFIC (group of disorders) | |
---|---|---|
Inheritance | Autosomal dominant | Autosomal recessive |
Incidence estimate | 1/30 000 to 1/50 000 live births 22 | 1/50 000 to 1/100 000 live births 12 |
Genetics |
|
|
Mechanisms of disease and pathophysiology underlying cholestasis |
|
|
Clinical presentation |
|
|
Disease progression |
|
Higher mortality estimates may reflect disease not treated by liver transplantation.
Abbreviations: ALGS, Alagille syndrome; BSEP, bile salt export pump; FXR, farnesoid X receptor; GGT, gamma‐glutamyl transpeptidase; MDR3, multidrug resistance protein 3; PFIC, progressive familial intrahepatic cholestasis.
Historical nomenclature; current naming convention is based on genetic disruption.
Other subgroups of low‐GGT PFIC are all very rare.
Lower mortality rates may be driven by high rates of liver transplantation (range, 40%‐100% among patients with ATP8B1 or ABCB11 deficiency).
3. BURDEN OF CHOLESTATIC LIVER DISEASES
Previous studies have shown that patients with ALGS or PFIC have impaired quality of life, physical health and psychosocial functioning based on patient or parent proxy reports relative to healthy controls. 29 , 30 Intractable pruritus has been identified as the most bothersome symptom of ALGS and PFIC; its marks can be visible as scratching‐induced abrasions and scarring. 9 , 18 , 31 Additional studies have highlighted that severe pruritus is associated with functional impacts such as interference with sleep or mood disturbance. 9 , 31 , 32
Liver transplantation is a common treatment for patients with ALGS or PFIC. The Global ALagille Alliance (GALA) study, which was described in a congress abstract reporting on a large cohort of patients with ALGS, found that 10‐year native liver survival was no more than 70%. 28 This is further illustrated in published data from 293 patients with ALGS and cholestasis in the multicentre, prospective Childhood Liver Disease Research Network (ChiLDReN) study, in which estimated liver transplant‐free survival was 24% at age 18.5. 33 The experience is similar for patients with PFIC. The 10‐year native liver survival among patients with ATP8B1‐ and ABCB11‐deficient PFIC, as reported by the NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) consortium, was 46%‐51%. 34 Additional analyses from the NAPPED consortium found that the time of median native liver survival varied by underlying genotype in ABCB11‐deficient PFIC; for example, certain missense mutations that produced BSEP with residual function were associated with a median native liver survival of 20.4 years, whereas mutations that completely disrupted the BSEP protein resulted in a median native liver survival of 3.5 years. 35 Healthcare costs in patients with PFIC and ALGS are likely considerable due to hospital visits and the need for long‐term care. 9 , 18
4. CURRENT TREATMENT LANDSCAPE AND OPPORTUNITIES FOR THERAPY
There are currently no approved drug treatments for either ALGS or PFIC. Medical treatment options are used supportively or for symptomatic relief and may include off‐label use of ursodeoxycholic acid (UDCA) to increase bile flow and reduce liver damage. 36 Other medications are used to manage pruritus 37 including cholestyramine, which sequesters bile acids in a resin complex for excretion 38 ; rifampin, which activates the nuclear pregnane X receptor and is thought to increase the elimination of bilirubin and enhance enzymatic reactions that make bile acids more hydrophilic and less toxic 39 , 40 , 41 ; naltrexone, an opioid antagonist used to decrease opioid‐mediated neurotransmission associated with pruritus and/or cholestasis 42 ; or antihistamines. In addition, a high‐calorie diet with vitamin/mineral supplementation (eg calcium, zinc and vitamins A, D, E and K) to provide nutritional support is frequently prescribed. 43 However, these approaches may not be entirely effective, and many patients either do not respond at all or require combination therapy. 6 , 44
Surgical options for treating ALGS and PFIC include surgical biliary diversion (SBD) and liver transplantation. 6 SBD, such as partial external biliary diversion (PEBD), may be performed in patients with severe pruritus that is not effectively managed with medications. 16 Liver transplantation is typically used for patients with end‐stage liver disease, with hepatocellular carcinoma (increased risk for its development in ABCB11 deficiency) or when other treatment options have been exhausted. 45 , 46 , 47 While SBD and liver transplantation are viable treatment options for ALGS and PFIC, post‐surgery issues such as the presence of a stoma (in the case of PEBD), the need for lifelong antirejection medication (in the case of transplant) or surgical complications may be practical limitations. 15 , 48 Less invasive treatment options that can reduce the accumulation of bile acids in the liver and potentially relieve pruritus and cholestasis, limit the progression of liver disease and improve long‐term prognosis would be valuable.
A number of alternative, nonsurgical therapies for cholestatic liver diseases, in general, are currently under investigation. These include modalities that target the FXR‐FGF19 signalling axis (eg FXR agonists, FGF19 mimetics, obeticholic acid), cholehepatic drugs (eg norUDCA) and enterohepatic blockers (eg IBAT inhibitors). 49 Compounds that act through FXR or FGF19 are proposed to stimulate bile acid transporter synthesis and the production of other gene products, with a cumulative effect of reducing intrahepatic bile acids level. 50 Another promising compound is norUDCA, a derivative of UDCA that protects cholangiocytes from bile acid injury. 50 These compounds have typically been evaluated in trials of cholestatic liver diseases in adults, and the benefits and risks to paediatric patients with ALGS and PFIC are unknown.
Potential therapies with specific applications for ALGS and PFIC include JAGGED1 small interfering RNAs and induced pluripotent stem cells (reviewed in Feldman and Sokol, 50 Morell and Strazzabosco, 51 and Hansel et al 52 ). In addition, there is a growing interest in IBAT inhibitors (currently in late‐stage clinical development for cholestatic liver diseases, including ALGS and PFIC) due to their specificity for IBAT in the intestine and their limited side‐effect profile outside the gastrointestinal system. IBAT inhibitors are the focus of the rest of this review.
5. INTERRUPTION OF THE ENTEROHEPATIC CIRCULATION AS A TREATMENT TARGET
Given that patients with ALGS and PFIC have intrahepatic accumulations of bile acids that can damage tissues in the liver and spill over into systemic circulation, SBD procedures were developed to interrupt enterohepatic circulation and reduce the bile acid pool in these patients. 8 , 15 SBD is often associated with reductions in serum bile acids and pruritus as well as improvements in sleep disturbance, quality of life, fibrosis and growth. 53 , 54 , 55 In the case of PFIC, most of the currently available data on SBD are based on ATP8B1‐ and ABCB11‐deficient patients. 20 , 48 , 54 , 56 , 57 , 58
Findings from the NAPPED consortium showed that patients with ABCB11 deficiency who underwent SBD (n = 61) typically had reduced pruritus and serum bile acids relative to pre‐surgery (pruritus was present in 97% of patients prior to surgery and in 46% after SBD; mean serum bile acids decreased from 363 μmol/L initially to 48 μmol/L after SBD). 35 Furthermore, a significant association was identified between lower post‐SBD serum bile acids and long‐term native liver survival: patients whose serum bile acids were <102 μmol/L after SBD survived up to 15 years with their native liver intact vs patients whose serum bile acids were ≥102 μmol/L, for whom less than half had this outcome. 35 Similarly, in a systematic review and meta‐analysis evaluating studies with pre‐ and post‐PEBD liver biochemistry values, patients with PFIC with reduced serum bile acids post‐PEBD were more likely to have favourable clinical responses (ie, improved pruritus, decreased need for liver transplant). 59 Thus, the reduction in bile acids and improvement in clinical outcomes observed with SBD provide a strong rationale that disrupting enterohepatic circulation holds promise for treating patients with cholestatic liver disease. Data from the NAPPED consortium also indicated that patient genotype, at least in the case of ABCB11‐deficient PFIC for which data are available, may influence long‐term outcomes following SBD; these data hint at a possibility for personalized medicine approaches in the future. 35
Inhibition of IBAT represents a pharmacologic approach for achieving the same ends as SBD: that is, interruption of the enterohepatic circulation of bile acids. IBAT is an integral brush border membrane glycoprotein that co‐transports sodium and bile acids and is a major regulator of the bile acid pool size in animals and humans. 60 IBAT inhibition prevents the intestinal reabsorption of bile acids to reduce bile acids in the liver and would be a nonsurgical alternative to SBD. Genetic ablation of IBAT in mice demonstrated that loss of IBAT function and the resulting redirection of bile acids to the colon cannot fully compensate for the increase in bile acid synthesis 61 ; based on this premise, selective IBAT inhibition is thought to produce a net reduction in the hepatic exposure to bile acids (Figure 1B). 3
One piece of evidence that IBAT inhibition could provide benefits similar to SBD is provided by a case report of a patient with ABCB11 deficiency. 62 This patient was treated with the IBAT inhibitor odevixibat in a phase 2 clinical trial 63 and experienced improvements in serum bile acids, pruritus and sleep. When the trial ended, the patient's symptoms returned. The patient subsequently underwent PEBD, which resulted in reductions in pruritus and serum bile acids and improvements in sleep similar to those achieved with prior IBAT inhibitor treatment, suggesting that in this patient, IBAT inhibition was as effective as PEBD for treating cholestasis. 62
6. IBAT INHIBITORS IN DEVELOPMENT
Key preclinical and clinical data for 5 IBAT inhibitors in development are summarized in Table 2. 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 All are selective, reversible small molecule inhibitors of IBAT, administered orally once or twice daily. Overall, study data supported the anticipated effects of IBAT inhibition, that is, decreased hepatic and circulating bile acid levels accompanied by increased fecal bile acid excretion. 82 , 83 , 84 , 85 , 86
Table 2.
IBAT inhibitors currently in development
IBAT inhibitor | Target indication(s) | Key preclinical findings | Key clinical findings | Current status | |
---|---|---|---|---|---|
Paediatric Cholestatic Liver Diseases | |||||
Maralixibat (LUM001; SHP625; lopixibat chloride) | ALGS; PFIC; BA (planned) |
|
|
||
Odevixibat (A4250) | PFIC; ALGS; BA |
|
|
|
|
GI, Metabolic and Other Hepatic Conditions | |||||
Elobixibat (A3309) |
Chronic constipation; NASH |
|
|
|
|
Linerixibat (GSK2330672) | Type 2 diabetes; cholestasis; PBC |
|
|
|
|
Volixibat (SHP626) | NASH; ICP; PSC |
|
|
|
Abbreviations: AE, adverse event; ALGS, Alagille syndrome; ALT, alanine aminotransferase; BA, biliary atresia; CNS, central nervous system; CV, cardiovascular; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; GI, gastrointestinal; GLP‐1, glucose‐dependent insulinotropic peptide; IBAT, ileal bile acid transporter; ICP, intrahepatic cholestasis of pregnancy; LDL, low density lipoprotein; MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cholangitis; PFIC, progressive familial intrahepatic cholestasis; PSC, primary sclerosing cholangitis; URTI, upper respiratory tract infection.
IBAT inhibitors are currently in development for a range of target indications across both paediatric (eg PFIC, ALGS and others) and adult (eg PBC, PSC, others) populations. In cholestatic liver diseases, preventing the return of bile acids to the liver via IBAT inhibition may relieve the inflammatory and fibrotic pressures driving tissue damage such that cholestasis and liver function may improve. 3 , 69 Because IBAT inhibition results in more bile acids redirected to the colon (which stimulates colonic motility), IBAT inhibitors are also being investigated to treat constipation. 87 Finally, because bile salts can act as signalling molecules via their interactions with nuclear receptors and downstream targets including genes involved in lipid and glucose metabolism, they may also be potentially useful in the treatment of metabolic disorders such as type 2 diabetes mellitus or nonalcoholic steatohepatitis (NASH). 88
Two IBAT inhibitors, maralixibat and odevixibat, have been evaluated in phase 2 and phase 3 clinical trials of paediatric patients with ALGS and PFIC; however, much of the available clinical data are from results thus far only presented at scientific congresses, with 1 exception for which data from a peer‐reviewed publication are available. 65 Maralixibat has been evaluated for ALGS in 2 phase 2 trials (ITCH 65 and IMAGO [some study results were included with ITCH study findings]) and in three additional long‐term phase 2 trials that are ongoing (ICONIC 66 , 89 and IMAGINE‐I 90 and –II, extensions of the IMAGO trial). In the ITCH trial, the group of patients with ALGS treated with the two highest doses of maralixibat did not show a difference from placebo on a measure of pruritus (assessed via the observer‐rated Itch Reported Outcome scale). 65 , 91 However, among all patients treated with maralixibat (3 dose groups combined), a greater proportion achieved a 1‐point pruritus score reduction than those who received placebo (68% vs 25%). The change from baseline in total serum bile acids for any maralixibat group was similar to the change observed with placebo. Gastrointestinal side effects were reported by approximately half of all patients treated with maralixibat, but none were severe. Additionally, maralixibat is being evaluated for PFIC in 2 long‐term studies: the phase 2 INDIGO 67 study and the phase 3 MARCH‐PFIC trial.
Odevixibat was evaluated as treatment for paediatric cholestatic liver diseases, including ALGS and PFIC, in a phase 2 study. 63 Key findings from this study include reductions in serum bile acids from baseline (with some patients experiencing up to a 98% reduction) and improvements in patient‐recorded pruritic and sleep disturbance symptoms (pruritus was assessed using 3 scales). 63 Overall, 7/24 patients reported any gastrointestinal adverse event, and all but 1 were mild or moderate in severity. A phase 3 study and its long‐term extension study evaluating odevixibat in patients with PFIC are underway (PEDFIC‐1 and PEDFIC‐2, respectively; PEDFIC‐2 also includes a cohort of patients with other types of PFIC).
IBAT inhibitors are also in clinical development for other cholestatic liver diseases and indications, for which phase 2 and 3 data are summarized below. For the studies described below, some data were available from published abstracts only, but the majority of data were available in peer‐reviewed publications. 73 , 74 , 75 , 77 , 78 , 92 , 93 , 94 , 95
Maralixibat has been evaluated in phase 2 trials for cholestatic liver disease in adults (PBC, 94 PSC 96 ), and a trial investigating maralixibat for biliary atresia is planned for 2020. 97 The phase 2 study of odevixibat described above also evaluated paediatric patients with other types of cholestatic liver disease, including those with diagnoses of biliary atresia, multidrug resistance protein 3‐deficient PFIC and other causes of intrahepatic cholestasis. 63 , 70 , 71 A trial investigating odevixibat for biliary atresia (BOLD; NCT04336722) started in 2020. 98 Furthermore, odevixibat was evaluated as treatment for adults with PBC. 95 Elobixibat is approved in Japan for the treatment of chronic constipation (supported by clinical data from a number of phase 2 73 , 92 and phase 3 74 studies), and is currently being explored in a phase 2 study of patients with either nonalcoholic fatty liver disease or NASH (NCT04006145); phase 2 studies indicated metabolic effects of elobixibat. 75 The IBAT inhibitor linerixibat demonstrated efficacy in reducing pruritus severity in adults with PBC. 77 In another phase 2 study, pruritus in patients with PBC was associated with elevated serum bile acids and autotaxin levels, and treatment with linerixibat reduced serum bile acids. 93 Linerixibat is currently being investigated in a phase 2 dose‐response trial of adults with PBC and pruritus (NCT02966834), and previously was evaluated in a phase 2 trial for type 2 diabetes. 78 The IBAT inhibitor volixibat did not meet the primary efficacy endpoint in a phase 2 trial for the treatment of NASH. 80 Finally, 2 trials to investigate volixibat in PSC and intrahepatic cholestasis of pregnancy are planned to initiate in 2020. Because bile‐modulating therapies including IBAT inhibitors are being explored for the treatment of PSC in adults, 99 , 100 IBAT inhibition may also be a potential therapeutic option in children with PSC; however, clinical studies are needed to determine efficacy and safety in this population.
7. CONCLUSIONS
ALGS and PFIC are rare, inherited childhood disorders that manifest with cholestasis and pruritus as well as progressive, life‐threatening liver disease. Limited treatments are available, and there are currently no approved pharmacologic therapies. Preclinical and clinical data support IBAT inhibitors as noninvasive options to interrupt the enterohepatic circulation to treat cholestatic liver diseases and other disorders. These orally administered, selective and reversible compounds decrease enteric bile acid reuptake with minimal systemic exposure. They may play an important role in reducing the symptoms of ALGS and PFIC by pharmacologically interrupting the enterohepatic circulation of bile acids, thus reducing bile acid accumulation in the liver and reducing the potential for hepatobiliary injury.
CONFLICT OF INTEREST
Binita Kamath is a consultant for Albireo, Mirum and DCI. Philip Stein is an employee of Albireo Pharma, Inc. Roderick Houwen is and/or was a consultant for the Dutch Medicine Authority and GMPOrphan, Univar, Albireo and Alexion. Henkjan Verkade is a consultant for Albireo, Ausnutria, Intercept, Mirum, Vivet, FrieslandCampina Dairy Foods, GMP‐Orphan and Shire.
ETHICS APPROVAL AND PATIENT CONSENT
Not applicable.
Kamath BM, Stein P, Houwen RHJ, Verkade HJ. Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020;40:1812–1822. 10.1111/liv.14553
Handling Editor: Emma Andersson
Funding information
Editorial and medical writing support were provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Albireo AB.
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