Tag Archives: Maralixibat

New Era in Cholestatic Liver Diseases

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H Sutton, RJ Sokol, BM Kamath. Hepatology 2025; 82: 985-995. Open Access! IBAT inhibitors in pediatric cholestatic liver diseases: Transformation on the horizon?

This review article is one of many in the same issue (#4) of Hepatology.

Key points:

  • “In the last few years, a novel class of agents, intestinal bile acid transporter (Ileal bile acid transporter (IBAT); also known as apical sodium-dependent bile acid transporter [ASBT]) inhibitors, has emerged and gained approval from the FDA… the pivotal studies on which these approvals were granted were all performed in rare pediatric cholestatic diseases, namely Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC).3 Additional expansion of these approvals will possibly follow as there are ongoing trials of IBAT inhibitors in primary biliary cirrhosis, primary sclerosing cholangitis, and biliary atresia.”
  • “The role of bile acids in promoting hepatic injury in cholestasis is perhaps best illustrated in human infants with ABCB11 (bile salt export pump; BSEP) disease or PFIC type 2…The response to IBAT inhibition in this disease further supports the notion that retained bile acids are a key factor leading to progressive liver injury and cholestatic symptoms including pruritus, fat-soluble vitamin deficiencies, and growth failure.4“
  • These medications may improve liver histology and not just reduce pruritic symptoms: “Using the MDR2−/− mouse cholangiopathy model, Miethke et al22 demonstrated that ASBT inhibition led to a reduction in both serum and intrahepatic bile acid concentrations by 98% and 65%, respectively. These reductions in bile acid concentrations were associated with improved liver biochemistry and a reduction in peri-portal inflammation and fibrosis on histology. The histopathologic improvements seen in these treated MDR2−/− are important to highlight, as they support the rationale of this therapeutic approach: that lowering serum bile acid (sBA) with IBAT inhibition leads to a reduction in intrahepatic bile acid accumulation and toxicity, improvements in liver inflammation and fibrosis, and ultimately improved liver disease biology.”
  • Numerous clinical trials are listed in Table 1 (completed trials) and Table 2 (ongoing).
  • Physiology: “Bile acids are key regulators of their own enterohepatic circulation, predominately through activation of the farnesoid X receptor (FXR)…the fecal elimination of bile acids in IBAT inhibitor–treated patients appears to far exceed the rate of synthesis of new bile acids in the liver; thus, IBAT inhibitors reduce the total bile acid pool size and the bile acid load presented to the liver.22,34,39“
  • Alagille syndrome (ALGS): Key trials are summarized including the ICONIC trial with maralixibat and the ASSERT trial with odevixibat.
  • PFIC (Type 1 and 2) Trials: Key trials are summarized including the MARCH-PFIC trial with maralixibat and the PEDFIC1 & PEDFIC 2 trialswith odevixibat.
  • Safety: These medications are well-tolerated with self-limiting diarrhea and abdominal pain especially at the initiation of these medications. Liver blood test abnormalities have been noted in up to 20%. “This is an interesting finding, and the underlying etiology is unknown. Maralixibat is largely luminally restricted and so, without systemic absorption, a direct hepatotoxic effect is unlikely. It may reflect an alteration in the speciation of the bile acid pool with increasing bile acid synthesis or alterations in the gut-liver axis signaling. More importantly, it is not known if there are any clinical consequences to the increase in ALT.”
  • Cost: The authors note that ursodeoxycholic acid and antihistamines are frequently used for management of pruritus. They also not that “from a cost standpoint, it seems appropriate to offer rifampin before IBAT inhibitors in the treatment of cholestatic pruritus.”
  • Conclusions: “The clinical trial data are encouraging. As more physicians gain experience prescribing IBAT inhibitors, we will continue to learn how to best apply them to our patient populations. Like any new drug, there are still several unknowns. One of these unknowns is the potential for loss of efficacy…The short-term to medium-term clinical effects of IBAT inhibitors are clear, but we have not yet begun to see the long-term benefits. Whether durable reductions in oncogenic and fibrogenic bile acids reduce rates of HCC or slow the progression of (or reverse) portal hypertension remains to be seen.”

Related article: M Trauner, SJ Karpen, PA Dawson. Hepatology 2025; 82: 855-876. Open Access! Benefits and challenges to therapeutic targeting of bile acid circulation in cholestatic liver disease

“Recent advances in understanding bile acid (BA) transport in the liver… This has led to new treatments targeting BA transport and signaling. These include inhibitors of BA transport systems in the intestine and kidney (IBAT/ASBT inhibitors) and liver (NTCP inhibitors), as well as receptor agonists that modify BA synthesis and transport genes. BA analogs like norucholic acid also show promise. This review discusses the molecular and clinical basis for these therapies, particularly for cholestatic liver disorders.

Principal therapeutic targets within the entero-nephro-hepatic circulation of BAs in cholestasis.

My take (borrowed from Trauner et al): “We have arrived at a new era in the treatment of cholestatic disorders. This has been made possible by incorporating findings from discoveries into the molecular pathogenesis of cholestasis and adaptive processes that direct rational therapeutics to improve patients’ lives.”

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Dr. William Balistreri: Whatever Happened to Neonatal Hepatitis (Part 2)

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Recently Dr. Balistreri gave our group an excellent lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

Key Points:

  • Producing enough bile acids and recycling bile acids in enterohepatic circulation is crucial for bile acid flow. In addition, there are ‘good’ bile acids like cholic acid that have trophic properties and ‘bad’ bile acids like lithocholic acid that cause liver toxicity
  • In addition to defects in the metabolic pathway of bile acids, discoveries identified defects in the membrane transporters (eg. FIC1, BSEP, MDR3), trafficking proteins (eg. MYO5B, VPS33B), nuclear control receptors (eg. FXR), and tight junction proteins (eg. TJP2). Tight junction protein defects are associated with bile leakage from bile canaliculus
  • Alagille syndrome, a disorder of embryogenesis, related to JAG1-NOTCH2 signaling pathways affects organs throughout the body
  • Many of these genetic mutations are now being identified in adults with unexplained liver diseases (eg. intrahepatic cholestasis of pregnancy and cryptogenic cirrhosis)
  • Cholestasis panels and whole exome sequencing are important tools
  • Ileal bile acid transporter (IBAT) inhibitors have emerged as important therapies for conditions like Alagille which were previously treated with biliary diversion

Cholestasis Evaluation:

See blog post: Identifying Biliary Atresia in Infants: New Guidelines

Baby with Carbamoyl-phosphate synthetase 1 (CPS1) deficiency (urea cycle defect)

My take: This lecture really shows how the field of pediatric liver disease has been a puzzle. Now one can see how almost all of the pieces of the puzzle work together.

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Relooking at 6-Year Data of Maralixibat for Alagille Syndrome

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BE Hansen et al. Hepatology 2024; 79: 1279-1292. Open Access! Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

This study compared “6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the Global ALagille Alliance (GALA) study.”

Based on a quick review, some the data appears to overlap a recent report in the same journal: RJ Sokol et al. Hepatology 2023; 78: 1698-1710. Open Access! Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor (See blog post: Six Year Data for IBAT Inhibitor Treatment for Alagille Syndrome).

In the current study, “event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods.”

Key findings:

  • Event-free survival in the maralixibat cohort (n=84) was significantly better than the GALA cohort (n=469) (HR, 0.305)
  • Transplant-free survival showed similar results (aHR, 0.33)

In their discussion, the authors note that much of the improvement in event-free survival is due to improvement in pruritus which is a main indication for liver transplantation. They speculate that improvement in event-free survival is also related to more broad-based clinical improvement (observed in ICONIC study), perhaps due to reduction in retained hepatic bile acids.

One of the limitations, reliance on a historical control, is discussed. “Historical control comparison is useful when there are ethical concerns regarding the recruitment of patients for long-term control arms requiring several years of study in life-threatening or debilitating diseases.”

My take: In this real-world comparison, Maralixibat, clearly was associated with improved outcomes. How much of this was due to relief of intractable pruritus and how much of this may be due to other biologic factors remains uncertain.

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Six Year Data for IBAT Inhibitor Treatment for Alagille Syndrome

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RJ Sokol et al. Hepatology 2023; 78: 1698-1710. Open Access! Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor

In this study, the authors examined 43 potential predictors of outcomes in pediatric patients (n=76) treated with maralixibat (MRX). The median duration of MRX treatment was 4.7 years. Key findings:

  • There were 10 liver transplantations, 3 decompensations, 2 deaths, and 1 surgical biliary diversion; thus, 16/76 (21%) had liver-related events.
  • The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival.
  • In this cohort, younger children (<36 months) fared worse, though this was likely related to selection bias as they had more severe cholestasis. In the discussion, the authors note that in their cohort, “there is a survivor bias such that older children are inherently healthier or they would have already undergone transplantation.”
  • Improved event-free survival could be largely related to symptomatic improvement. Many kids with Alagille require transplantation due to refractory pruritus. Since this study did not include histology or noninvasive techniques to assess hepatic fibrosis, it is unclear if there was also improvement in underlying liver function/fibrosis subsequent to reduction in toxic bile acid retention.
  • 46/76 (61%) had improvement in pruritus, 52/76 (68%) had improvement in bilirubin, and 56/76 (74%) had improvement in serum bile acids.

In their discussion, the authors note that in the GALA study, “which included natural history data from >1400 patients, 358 patients required a liver transplant, with 69% being transplanted for intractable pruritus.4“

My take: In patients with moderate to severe pruritus, patients who respond to IBAT inhibitors are likely to have improvement in important clinical outcomes.

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Lecture: IBAT Inhibitor for Alagille Syndrome

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I recently attended an online lecture which reviewed Alagille Syndrome and the emergence of an IBAT inhibitor for the management of cholestatic pruritus. Selected slides from Mirum Pharmaceutical Lecture: “Updates in the Treatment of Cholestatic Pruritus in Patients With Alagille Syndrome.” *I have no financial disclosures or conflict of interests in this medication or company.

  • The severe itching which is seen in most patients with Alagille is often quite detrimental to quality of life. It impacts sleep, causes irritability, skin damage, and physical distcomfort
  • Typically, the first week of receiving the medication, it is started at1/2 the maintenance dose.
  • Monitoring response can be done with the ItchCheck App, Itch score or Clinical scratch score
  • Monitoring hepatic blood tests and periodic monitoring of fat soluble vitamins is recommended

My take: Though Alagille syndrome is a multisystem disease, improvement in pruritus due to cholestasis with an oral daily medication is an important advance/option. There is little systemic absorption and thus far a reassuring safety profile.

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Aspen Webinar 2021 Part 3-IBAT Inhibitors

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This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. Another great lecture from Dr. Suchy.

IBAT Inhibitors Frederick Suchy

Key  points:

  • IBAT inhibitors block intestinal absorption of bile acids/disrupt enterohepatic circulation; this leads to augmented bile acid excretion in stools
  • IBAT inhibitors may reduce liver damage in the setting of cholestasis/accumulation of toxic bile acids
  • Potential diseases for IBAT inhibitors include Alagille syndrome and PFIC
  • Van Wessel et al (J Hepatol 2020; 73: 84-93) correlated survival with PFIC1/PFIC2 with bile acid levels and showed improvement in survival in those with surgical biliary diversion
  • Goals for IBAT inhibitor trials: improvement in pruritus, bile acids, reduced ALT, hepatic fibrosis, HCC and need for liver transplantation
  • Marixibat is available for use as an FDA approved breakthrough medication for Alagille and PFIC2 in pediatric patients older than 1 year
  • Odexibat is designated as an orphan drug for Alagille, PFIC, PBC, and biliary atresia
  • Safety appears good with IBAT inhibitors. Fat soluble vitamin monitoring is needed
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Case report: Alejandro Velez Lopez

3 yo presented with fatigue and jaundice, 3 weeks after COVID-19 infection. She was not taking any medications.  Labs:  ALT 939, AST 1321, T bili 5.5, D bili 0.9, INR 2, Plts 174, Hgb 12.8, LDH 1297. remained positive for SARS-CoV2 by PCR. Acetaminophen -no exposure.  Evaluation: LKM 1:1280. Neg ANA, NL Ferritin, NL sIL2r, Other viral studies negative, NL IgG. Developed encephalopathy with NH4 317, INR peaked at 2.8.  Treated with steroids, rifaximin and lactulose.  Liver biopsy showed sub-massive necrosis and fibrosis (indicative of  autoimmune hepatitis, likely triggered or exacerbated by COVID-19).  Patient responded to medical therapy and did not require liver transplantation.

NASPGHAN Alagille Syndrome Webinar

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​A great and short webinar was recently presented from the ​NASPGHAN Foundation​ with three lectures

Webinar​​: Alagille Syndrome (If this link does not work, the On Demand version of the webinar is now available on LearnOnLine, at https://learnonline.naspghan.org/products/on-demand-advances-in-diagnosis-and-treatment-of-alagille-syndrome.  You can also find it by logging into LearnOnline at https://learnonline.naspghan.org/ and entering the Webinars section.)

The first lecture by Dr. Melissa Gilbert was an excellent overview of the genetics of Alagille Syndrome.

Key points:

  • JAG1 mutations account for ~95% of Alagille syndrome mutations and NOTCH2 about 3%
  • Many mutations identified are due to missense mutations which are often variants of unknown clinical significance (VOUS). In these patients, to determine if it is pathogenic, one has to correlate the clinical picture along with specific amino acid change, location of variant, and frequency of variant in normal population. Dr. Gilbert noted that among the ~97% of cases with genetic abnormalities, about 80% have recognized pathogenic mutations and about 17% have VOUS.
  • There is variability of severity of Alagille syndrome in the same family, likely related to genetic modifiers
  • When using genetic panel, if panel uses only single nucleotide variants, this will miss the deletion/duplication variants which account for ~10% of cases

The second lecture by Binita Kamath was a terrific review and compared the differences between Alagille Syndrome with JAG1 mutations and NOTCH2; the latter are much less likely to have cardiac abnormalities and butterfly vertebrae. The liver phenotype/survival is similar.

Key points:

  • Outcomes of Alagille syndrome by 25 years of age including frequent bone fractures and development of portal hypertension.
  • Severe liver disease is common. 75% in a multi-center cohort (CHILDREN) required liver transplantation by age 18 years and 10% died; in contrast, a large GALA cohort of 911 children, 41% survived with their native liver at 18 years.
  • After transplantation, renal sparing strategies are needed due to frequent renal insufficiency; patients with severe cardiac disease may not be candidates for liver transplantation.
  • There is work on an Alagille Syndrome growth curve.
  • Screening for brain vascular malformations/Moyamoya –Dr. Kamath tends to screen after age 8 years of age at baseline (when child does not need sedation for brain imaging) and then every 4-5 years. Also, an MRI/MRA is done prior to major surgery.
  • Hyperlipidemia in Alagille Syndrome is mainly due to lipoprotein X; this is not a risk factor for cardiac health.

The third (& also excellent) lecture by Saul Karpen (who disclosed his potential conflicts of interest) reviewed current treatments and emerging treatments.

Key points:

  • The current medical therapies have not been carefully tested; rifampin for pruritus may relieve cholestasis in about 50% of patients.
  • IBAT inhibitors interrupt enterohepatic circulation. These agents improve pruritus and decrease serum bile acids.
  • Dr. Karpen reminded the audience to follow fat soluble vitamin levels and if treatment is needed, to provide Vitamin D formulations with TPGS.
On the right hadd panel (above), the orange bar represents those with severe pruritus and the effects of PEBD on pruritus.

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