IBAT Inhibitors: The Medication That Patients With Pruritus Were Itching to Try

William F. Balistreri, MD


May 23, 2022

Pruritus is a prime clinical expression of cholestatic diseases in children and adults.

In my clinical experience, there was no more poignant depiction of the ravages of cholestatic pruritus than that of an 11-year-old girl with Alagille syndrome whom I saw many years ago.

She was brought to our clinic by her parents who were seeking relief for the unrelenting itching — so devastating that she was unable to sleep at night and was therefore unable to stay awake during school. Her grades were consequently affected.

The problem was apparent as soon as I walked into the room and saw a thin, preadolescent incessantly rubbing her back and arms against the fabric on the wall to ease the itching. On examination, the skin on her arms, legs, back, ear, and face was excoriated with numerous bleeding scratch marks.

We reviewed her current "antipruritic regimen," a varying combination of antihistamines and mild sedatives along with a generous dose of ursodeoxycholic acid. Her primary gastroenterologist had even referred her to a dermatologist who recommended ultraviolet-B light therapy, based on the observation that patients with pruritus experience less itching during sunlight exposure.

Unfortunately, none of these approaches solved the problem. Out of desperation, we recommended partial external biliary diversion, an operation that had been reported in patients with another form of cholestatic pruritus.

This scenario, while an extreme example, is not atypical. Similar symptoms are noted in patients with all forms of cholestasis. In this article, we focus on two forms of inherited cholestatic disease to illustrate the impact and options.

Manifestations and Clinical Impact of Cholestatic Pruritus

The main pathophysiologic manifestation of Alagille syndrome and various forms of progressive familial intrahepatic cholestasis (PFIC) is inadequate bile secretion, with intrahepatic accumulation of bile acids and other potential toxins.

The clinical manifestations may include severe chronic cholestasis manifesting as jaundice, unrelenting pruritus, and subcutaneous lipid deposits secondary to hypercholesterolemia (xanthomas). Intractable pruritus can lead to self-mutilation, scarring, sleep deprivation, and mood disturbance, severely reducing quality of life and often causing family disruption.

Unrelenting pruritus with cholestasis has been reported to have a major impact on the health-related quality of life (HRQOL) of patients and their caregivers. This includes physical and psychosocial domains, as also reported in parent proxy assessments of the HRQOL of their child.

A retrospective, cross-sectional study documented the significant burden on HRQOL among caregivers of those with this condition. Investigators noted impairment in all daily activities, reduced sleep duration, altered work productivity, financial consequences, career challenges, and strained relationships.

The caregivers participating in this study cited the "scarce available management approaches" as a major factor contributing to the heavy burden, something that could only be addressed by novel therapeutic approaches.

Management Strategies: Traditional and Emerging

There are no drugs specifically approved for the management of pruritus associated with cholestasis.

Medical treatment strategies target symptomatic relief of pruritus via off-label use of medications, such as the commonly prescribed ursodeoxycholic acid (which increases bile flow), cholestyramine (a bile acid sequestrant), naltrexone (an opioid antagonist), antihistamines (hydroxyzine, diphenhydramine, chloral hydrate), and rifampin.

Part of the reason for the lack of efficacy of these options relates to an imprecise understanding of the pathophysiologic mechanisms of cholestatic pruritus. Traditionally, accumulated bile acids have been implicated directly or indirectly; however, significant correlations have recently been observed between pruritus and serum autotaxin levels. Autotaxin is an enzyme involved in the production of lysophosphatidic acid, another possible mediator of pruritus.

Due to the lack of effective pharmacotherapy, several surgical approaches have been advanced that are directed toward interruption of the enterohepatic circulation of bile acids. However, clinical evidence suggests that the efficacy of partial biliary diversion and ileal exclusion is variable, and the burden of a lifelong stoma is significant.

A Novel Therapeutic Concept

The ileal bile acid transporter (IBAT), also designated as the apical sodium-dependent bile acid transporter, is an integral brush border membrane glycoprotein that co-transports sodium and bile acids. IBAT governs the resorption of bile acids from the distal intestine, allowing enterohepatic recirculation back to the liver.

Theoretically, IBAT inhibition is a pharmacologic analogy of surgical interruption of the enterohepatic circulation of bile acids; the net effect is similar: a decrease in serum bile acid levels and in the bile acid pool size. Selective IBAT inhibition has been reported to reduce the degree of hepatic exposure to bile acids with a reduced potential for hepatobiliary injury.

Clinical trials investigating IBAT inhibitors, conducted in adults with cholestatic pruritus, have reported a reduction in the intensity of pruritus compared with placebo.

Pediatric Trials

Two IBAT inhibitors, odevixibat and maralixibat, have been evaluated in clinical trials of pediatric patients with cholestatic pruritus associated with Alagille syndrome and PFIC. These potent nonsystemic, selective, reversible IBAT inhibitors act locally in the small intestine with minimal systemic exposure. IBAT inhibition leads to increased loss of bile acid via fecal excretion, with a reduction in the serum levels of bile acids.


The safety, tolerability, and efficacy of this IBAT inhibitor was evaluated in pediatric patients with cholestatic liver disease and pruritus in a phase 2, open-label, multicenter study. Children received odevixibat orally daily for 4 weeks.

Patient-reported diary data documented reduced pruritus and improved sleep.

The authors noted significant correlations between autotaxin and pruritus at baseline, with documented reductions in both itching and serum autotaxin levels after treatment with odevixibat.

No treatment-related serious adverse events were reported; minor adverse events, including diarrhea, vomiting, abdominal pain, and increased aminotransferase levels, were transient.

Although this study was limited by the lack of a placebo control, short treatment duration, and a heterogeneous patient population, the results are encouraging.

Preliminary data from randomized phase 3 trials conducted by Thompson and colleagues, and presented in abstracts at the Liver Meeting 2020, indicated that odevixibat was effective in reducing pruritus in children with PFIC and demonstrated long-term clinical benefit.

Odevixibat (Bylvay) received approval in July 2021 from the US Food and Drug Administration (FDA) for the treatment of pruritus in patients aged 3 months and older with PFIC.


Maralixibat, a small-molecule selective IBAT inhibitor, is also available as an oral, minimally absorbed agent.

Gonzales and colleagues evaluated the safety and efficacy of maralixibat for children with cholestasis associated with Alagille syndrome in a placebo-controlled, randomized withdrawal period, phase 2b study. Children received maralixibat once per day for 18 weeks and were then randomly assigned to continue maralixibat or receive placebo for 4 weeks.

In the initial phase, all participants reported a decrease in the severity of pruritus. Those who switched to placebo had a significant rebound increase in pruritus, whereas those who continued maralixibat maintained the established treatment effect. Maralixibat was found to be safe and well tolerated, although there were mild to moderate self-limited gastrointestinal adverse effects.

In another clinical trial, children with Alagille syndrome were randomly assigned to double-blinded administration of placebo, or varying dosages of maralixibat, for 13 weeks. Although many of the prespecified primary analyses of reduction in itch intensity did not reach statistical significance, the data suggested that maralixibat is safe and may reduce pruritus.

In preliminary reports published in 2019 and 2021, maralixibat was shown to reduce pruritus in a proportion of patients with PFIC associated with bile salt export pump deficiency (PFIC type 2).

Maralixibat (Livmarli) received approval from the FDA in September 2021, for use in the treatment of cholestatic pruritus in patients aged 1 year and older with Alagille syndrome.

Bottom Line

Although both IBAT inhibitors were approved for use in patients with severe pruritus on the basis of results of the small studies cited above, ongoing clinical trials and real-world experiences are needed to further assess their efficacy and safety in cholestatic diseases. This includes an understanding of the incidence and impact of the potential adverse events, including diarrhea, nausea, bloating, and elevations in serum aminotransferase levels, noted in the initial clinical trials.

In addition, with prolonged therapy it will be important to monitor for the potential effect of bile acid depletion, specifically fat-soluble vitamin deficiencies and growth.

Despite these limitations, these drugs clearly offer hope for our patients with the persistent, vexing symptom of intractable cholestatic pruritus.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, Liver Transplantation; and professor, University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center. He has served as director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for Medscape. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

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