Exploring Maralixibat for Treatment-Resistant Pruritus in Intrahepatic Cholestasis of Pregnancy and Primary Biliary Cholangitis: A Case Report

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a rare disorder that affects approximately 0.1% to 2% of pregnancies [1,2]. The condition typically manifests during the third trimester [3]. It is characterized by impaired bile flow and accumulation of serum bile acids (sBA) in the liver, leading to symptoms such as intense pruritus – particularly on the palms of the hands and soles of the feet – jaundice, and elevated liver enzyme levels [3,4]. Diagnosis requires the presence of pruritus and elevated sBA (≥10 μmol/L) after exclusion of other causes; normalization of these findings postpartum supports the diagnosis [3].

ICP develops due to a combination of genetic susceptibility, hormonal changes during pregnancy, and impaired hepatobiliary transport. Preexisting hepatobiliary disease further decreases hepatic reserve and increases vulnerability to cholestasis, although the exact mechanism remains unclear [3,5–7]. The incidence of ICP in patients with preexisting hepatobiliary disease is up to twofold higher than the incidence among individuals without this preexisting condition [6]. In some cases, ICP reveals previously undiagnosed autoimmune or cholestatic liver disorders [3]. An elevated long-term risk of hepatobiliary disease has also been observed after an ICP diagnosis [6].

ICP is associated with adverse maternal and fetal outcomes that vary according to sBA levels. These include intrauterine death (up to 3.4% higher risk), meconium-stained amniotic fluid (up to 44% higher risk), preterm birth before 37 weeks (up to 30% higher risk), and neonatal intensive care unit admission (up to 20.8% higher risk) [8,9]. These risks considerably increase after 37 weeks of gestation [10]. In a large study of more than 5,000 pregnancies affected by ICP, Ovadia et al found that rates of stillbirth were 0.13% for sBA levels between 0 and 39 μmol/L, 0.28% for levels between 40 and 99 μmol/L, and 3.44% for levels exceeding 100 μmol/L [9]. sBA concentrations greater than 100 μmol/L have been associated with a substantially increased risk of stillbirth, and labor induction is recommended when this threshold is exceeded [3].

Treatment is currently symptomatic, and ursodeoxycholic acid (UDCA) represents the first-line option. UDCA modifies the composition of the bile acid pool by replacing more hydrophobic and potentially toxic bile acids, such as chenodeoxycholic acid and deoxycholic acid [11]. This shift reduces the hepatotoxic effects of endogenous bile acids [11]. UDCA is considered safe during pregnancy and may help decrease the risk of complications [12–15]. There is no evidence to support additional treatments (e.g., cholestyramine, rifampicin, or activated charcoal), despite their frequent use [14]. Ultimately, delivery remains the only definitive intervention that resolves cholestasis and prevents fetal complications [3].

Novel therapeutic strategies for pruritus in cholestatic liver disease include ileal bile acid transporter (IBAT) inhibitors, such as maralixibat (Livmarli®, Mirum Pharmaceuticals). These agents block the apical sodium-dependent bile acid transporter [16], thereby preventing bile acid reabsorption in the terminal ileum, interrupting enterohepatic circulation, and reducing the total bile acid pool [16,17]. This mechanism directly targets the pathophysiologic driver of pruritus in ICP – elevated sBA – offering a potential therapeutic option for patients with treatment-resistant symptoms. Elimination primarily occurs via fecal excretion, which contributes to its characteristic adverse effect profile, most notably diarrhea [18]. Gastrointestinal symptoms, including abdominal pain and bloating, occur in up to 90% of patients. These effects are generally mild to moderate, although they occasionally lead to treatment discontinuation [19–21]. Due to the selective local action of IBAT inhibitors – mainly within the epithelial cells of the terminal ileum – and minimal systemic absorption, plasma concentrations are negligible and typically below the limit of quantification (0.25 ng/mL) in most samples [18,22,23].

Maralixibat has recently received regulatory approval from both the United States Food and Drug Administration and the European Medicines Agency for the treatment of Alagille syndrome and progressive familial intrahepatic cholestasis type 2 [22–24]. Ongoing clinical trials are evaluating its potential use in other cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis [20,21].

Due to their negligible systemic absorption, fecal excretion, and primarily luminal action, along with favorable effects in reducing the bile acid pool and alleviating cholestatic pruritus, IBAT inhibitors have been evaluated for the treatment of ICP [18,25,26]. A recent placebo-controlled study investigating volixibat, another IBAT inhibitor, among patients with ICP-associated elevated sBA was terminated due to enrollment challenges (only 4 participants were included) [26].

Encouraging results have been reported by Rodriguez et al, who described the use of maralixibat in a patient with benign recurrent intrahepatic cholestasis and exacerbated pruritus during pregnancy [25]. Maralixibat was well tolerated; it resulted in reduced pruritus and sBA stabilization below the critical threshold of 100 μmol/L [25]. The present report describes a 34-year-old woman who exhibited jaundice and pruritus at 19 weeks of gestation due to ICP/PBC overlap; these symptoms were managed with maralixibat.

Case Report

A 34-year-old woman presented at 19 weeks of gestation with jaundice and severe pruritus (Visual Analog Scale [VAS] score, 8/10). Mild symptoms had begun around the fourth week of pregnancy. Her obstetric history included 2 prior pregnancies, both uneventful except for gestational diabetes and hypertension. Her medical history included obesity (body mass index, 40 kg/m2) and a previous cholecystectomy; she had no history of tobacco smoking, alcohol consumption, or substance abuse. On clinical examination, the patient was in good general condition with normal vital parameters but exhibited jaundice and icteric sclerae. Notable findings included visible excoriation marks without signs of eczema or pustular lesions. Initial laboratory investigations revealed a mixed pattern of hepatopathy, characterized by alkaline phosphatase (ALP) levels exceeding 3 times the upper limit of normal (ULN), up to 300 U/L (ULN 129); alanine aminotransferase (ALT), approximately 223 U/L (ULN 50); aspartate aminotransferase (AST), up to 220 U/L (ULN 50); gamma-glutamyl transferase, initially within normal range (12 U/L); and mildly elevated bilirubin (50 μmol/L; ULN 21). sBA levels were substantially increased, exceeding 20 times the ULN, with an initial value of 213 μmol/L (ULN 10) (Table 1). Hematologic parameters were within normal limits, and there was no evidence of hemolysis (hemoglobin, 121 g/L; white blood cells, 9.5×109/L; eosinophils, 0.12×109/L; platelets, 306×109/L). Fasting glucose, urea, renal function, glycated hemoglobin (5.6%), and coagulation profiles were unremarkable. Viral serology results for hepatitis B, C, and E, and human immunodeficiency virus were negative. Abdominal ultrasonography showed no evidence of cholestasis, hepatic perfusion abnormalities, or clinically significant steatosis.

Diagnostic criteria for pregnancy-specific disorders, including HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) and acute fatty liver of pregnancy, were not met; there was no evidence of hemolysis, thrombocytopenia, encephalopathy, or coagulopathy, and Swansea criteria were negative. However, the clinical presentation – early onset and progressive pruritus during gestation combined with elevated sBA – was compatible with ICP. Autoimmune serological markers, including anti-M2 antibodies (220 IU/mL; ULN 4 IU/mL), anti-mitochondrial antibodies (1: 640; ULN 1: 40), IgM (2.9 g/L; ULN 2.8), anti-nuclear antibodies (1: 1280; ULN 1: 80), and anti-GP210/anti-SP100 dual positivity, fulfilled established diagnostic criteria for PBC [27]. A liver biopsy was not performed due to procedural risk and fulfillment of established serological criteria.

In summary, the patient presented with severe pruritus and markedly elevated sBA levels attributable to PBC-associated ICP. Given the established relationship between elevated sBA and fetal risk, therapeutic strategies were directed toward reducing sBA levels and alleviating maternal symptoms.

Treatment with UDCA (500 mg, 3 times daily) was initiated at 19 weeks of gestation, leading to improvement in biochemical cholestasis but providing minimal relief of pruritus. Additional therapies with levocetirizine and topical agents (cold cream, in-house fat cream, Optiderm®) failed to alleviate symptoms. Cholestyramine was subsequently added, resulting in a reduction in sBA levels from 121 μmol/L to 48 μmol/L. However, the pruritus persisted unchanged, with a VAS score of 8/10 (Figure 1).

Given the patient’s persistent severe pruritus and substantial impairment in quality of life despite optimized standard therapy – including UDCA, antihistamines, topical treatments, and cholestyramine – further therapeutic escalation was considered medically necessary. Due to the refractory nature of the symptoms and lack of effective alternatives, the severity of suffering justified off-label administration of an IBAT inhibitor under compassionate use. The decision was made after a detailed risk-benefit assessment and thorough informed consent process. The primary goal was to relieve the patient’s debilitating symptoms while minimizing fetal risk. The patient provided consent at 30 weeks of gestation; maralixibat therapy was initiated at a dose of 190 μg/kg/day and doubled after 1 week. Within 2 weeks, pruritus substantially improved, such that the VAS score decreased from 8/10 to 0–3/10. The treatment was well tolerated; however, at the higher dose of 380 μg/kg/day, diarrhea developed and dose reduction was required. Despite subsequent adjustment to 250 μg/kg/day, the pruritus was well controlled (VAS 0–3/10), and sBA levels remained below 100 μmol/L until late gestation (Figure 1).

The introduction of maralixibat was associated with stabilization of sBA, transaminase (AST, ALT), and bilirubin levels, although ALP levels continued to rise during therapy. At 35+6 weeks of gestation, an increase in sBA to 110 μmol/L prompted induction of labor due to the known risk of adverse fetal events above this threshold. The child was delivered vaginally with good postnatal adaptation (birth weight, 2110 g; Apgar scores, 9/9/10). Both mother and infant were clinically well. Maralixibat was discontinued 2 days postpartum, whereas UDCA therapy was continued. According to the mother’s verbal report, the newborn was monitored during routine pediatric evaluations. No systematic neonatal investigations were performed – no fetal effects were anticipated given the pharmacokinetic properties of IBAT inhibitors.

Discussion

This case highlights the potential role of maralixibat as adjunctive therapy for severe, treatment-resistant pruritus in ICP and overlapping cholestatic liver diseases, such as PBC. The coexistence of these conditions underscored both the diagnostic complexity and the therapeutic limitations encountered in clinical practice.

Our patient presented with severe, treatment-resistant ICP, and pregnancy had unmasked previously undiagnosed PBC. Despite optimized standard therapy with UDCA and cholestyramine, pruritus remained debilitating, and sBA levels only partially improved. Initiation of adjunctive maralixibat resulted in substantial reduction of pruritus (VAS 8/10 to 0–3/10) and stabilization of sBA concentrations below the critical threshold of 100 μmol/L until late gestation. Although the early onset and exacerbation of symptoms during the second trimester were consistent with ICP, the persistence of elevated sBA levels and pruritus after delivery indicated underlying PBC that became clinically apparent during pregnancy. Taken together, these findings emphasize the diagnostic and therapeutic challenges inherent in ICP, particularly when complicated by concomitant autoimmune liver disease.

The management of ICP remains challenging due to its associated maternal and fetal risks [3]. UDCA is the recommended pharmacologic intervention for ICP [3], supported by meta-analyses demonstrating moderate improvements in liver function and pruritus; however, evidence for improved perinatal outcomes remains inconsistent [13,15]. According to a meta-analysis by Kong et al, UDCA significantly improved pruritus (risk ratio, 1.68; 95% confidence interval [CI], 1.12–2.52) and reduced sBA levels (standardized mean difference, −0.68; 95% CI, −1.15 to −0.20) [15]. However, a Cochrane Review concluded that although UDCA slightly reduced pruritus (mean difference, −7.64 points on a 100-mm VAS), this reduction may fall below the threshold of clinical relevance for many patients [14]. Furthermore, an individual participant data meta-analysis revealed no significant decreases in stillbirth or composite perinatal outcomes overall, although subgroup analysis suggested potential benefit in severe cases with sBA levels at or above 40 μmol/L (adjusted odds ratio for composite outcome in randomized controlled trials, 0.60; 95% CI, 0.39–0.91) [13]. These findings indicate that whereas UDCA contributes to biochemical improvement, its effects on clinically meaningful outcomes – particularly pruritus relief and fetal protection – remain limited.

Alternative therapies such as rifampicin and cholestyramine have been considered in UDCA nonresponders, but their efficacy lacks robust clinical trial support [14]. In contrast, IBAT inhibitors have shown promising effects in pediatric and adult cholestatic liver diseases, including Alagille syndrome, progressive familial intrahepatic cholestasis type 2, and primary sclerosing cholangitis; they also have been evaluated for PBC [19,21,22,28]. In a randomized phase 2 trial by Gonzales et al involving patients with Alagille syndrome, maralixibat achieved a mean reduction in pruritus score on the Itch Reported Outcome (ItchRO™) of −1.6 points (95% CI, −2.1 to −1.1), with sustained benefit through 204 weeks in long-term extension studies; mean sBA levels at week 48 had improved from baseline by −96 μmol/L (95% CI, −162 to −31) [29]. In patients with primary sclerosing cholangitis, maralixibat treatment over 14 weeks resulted in a mean pruritus reduction of up to 70% among those with moderate-to-severe baseline symptoms (ItchRO™ daily average score ≥3) [21]. Mean sBA levels decreased by 40% (−22.3 μmol/L; 95% CI, −40.38 to −4.3; P=0.004) by week 14 in participants with elevated baseline sBA [21]. However, in a randomized, placebo-controlled phase 2 trial by Mayo et al encompassing patients with PBC, maralixibat produced a mean reduction in the ItchRO™ weekly sum score of −26.5 points over 13 weeks, compared with −23.4 points in the placebo group. The difference between maralixibat and placebo in pruritus improvement was not statistically significant (P=0.48), although sBA levels decreased by −17.0 μmol/L (95% CI, −36.9 to 2.9) during treatment [20].

Data regarding the use of IBAT inhibitors during pregnancy remain limited. Based on pharmacokinetic studies, agents such as maralixibat exhibit minimal systemic absorption [18,22,23].

In a phase 1 study of volixibat, another IBAT inhibitor labeled with a radioactive tracer, no radioactivity was detected in plasma or whole blood; plasma concentrations of volixibat remained below 0.18 ng/mL, with a mean effectively at zero. More than 92% of the administered dose was recovered unchanged in feces, whereas only 0.01±0.007% appeared in urine, confirming that the compound primarily remains within the intestinal lumen [18]. Comparable data for maralixibat demonstrate negligible plasma concentrations [23]. In the context of pregnancy, the pharmacokinetic profile of IBAT inhibitors indicates negligible fetal exposure because placental transfer is highly unlikely without measurable maternal systemic levels. This suggests a potentially favorable safety profile with respect to fetal exposure [18,23]. However, no controlled studies have yet evaluated the use of IBAT inhibitors during pregnancy. A clinical trial of volixibat in ICP was terminated prematurely due to recruitment challenges and was closed after enrollment of only 4 patients [26]. Recently, a case report by Rodriguez et al described the use of maralixibat in severe, therapy-resistant ICP associated with benign recurrent intrahepatic cholestasis [25]. Maralixibat reduced peak sBA by 67% (from 269 to 89 μmol/L), prevented the 100 μmol/L risk threshold from being exceeded, and led to a timely, uncomplicated outcome, although vitamin deficiencies were observed [25].

In our case, consistent with established ICP management, UDCA was administered as the primary therapeutic intervention. Treatment with UDCA, followed by combination therapy with cholestyramine, improved liver function tests and reduced sBA levels (Figure 1). However, the antipruritic effects of UDCA and the combination regimen were limited in this patient. The lack of efficacy in alleviating pruritus, absence of alternative therapeutic options [14], and emerging evidence regarding the use of IBAT inhibitors such as volixibat and maralixibat in ICP [25,26] prompted consideration of maralixibat, despite the limited data available regarding its use in this context.

In the present case, maralixibat was associated with a rapid and clinically meaningful improvement in pruritus severity. The only adverse event observed was diarrhea, which resolved after dose reduction. The treatment was administered for 6 weeks until delivery, without detectable adverse effects on the newborn.

Although serum sBA levels had already decreased with UDCA and were further reduced by cholestyramine, pruritus remained unchanged during that phase of treatment. The notable and rapid improvement in pruritus (VAS score, 8/10 to 0–3/10) occurred only after the initiation of maralixibat, suggesting an additional effect beyond biochemical cholestasis control. Nonetheless, a delayed, synergistic, or cumulative influence of prior therapies cannot be excluded, and the temporal sequence alone does not allow definitive attribution. ALP levels continued to rise steadily throughout the treatment course, including after maralixibat initiation (Table 1). Because UDCA can represent up to 60% of total sBA levels during treatment [11], its use may have contributed to the persistent elevation of ALP. This pattern also supports the hypothesis that underlying PBC independently contributed to the biochemical profile.

This report has inherent limitations. First, it represents a retrospective observation without a predefined protocol or standardized assessment instruments. The evaluation of pruritus was based on clinical judgment and patient-reported VAS scores; laboratory monitoring did not include measurement of fat-soluble vitamin levels, which could have provided additional insights into safety. Second, given the single-patient observational design and lack of a comparator group, the improvement in pruritus cannot be definitively attributed to maralixibat alone – cumulative or synergistic effects of prior therapies cannot be excluded. Finally, the generalizability of the findings remains limited, emphasizing the need for systematic studies to clarify the safety and efficacy of IBAT inhibitors in ICP.

Conclusions

Maralixibat appeared to be well tolerated and effective as adjunct therapy for severe, treatment-resistant pruritus in a pregnant woman with ICP/PBC overlap; there was no evidence of relevant adverse effects in either the mother or the child during short-term follow-up. The use of an IBAT inhibitor aligns with emerging strategies targeting enterohepatic bile acid circulation to manage cholestatic pruritus. Although well tolerated in this instance, the absence of systematic safety data during pregnancy underscores the need for controlled studies to evaluate the safety and efficacy of IBAT inhibitors in pregnant populations.