EXPAND Phase 3 Win Opens Biliary Atresia Door, But Label Scope and HTA Ceiling Remain Unresolved

Mirum's LIVMARLI Meets Primary Endpoint in Phase 3 EXPAND Study

Mirum Pharmaceuticals announced positive topline results from its Phase 3 EXPAND study of LIVMARLI (maralixibat) for cholestatic pruritus in patients aged 6 months or older with ultra-rare cholestatic liver diseases, including biliary atresia. The study met its primary endpoint, demonstrating a statistically significant improvement in pruritus with a mean 1.81-point reduction from baseline in average worst-daily ItchRO(Obs) severity score for maralixibat versus 0.83-point for placebo (p=0.0004). Maralixibat also achieved a 70.1% reduction from baseline in serum bile acids compared to 3.5% for placebo (p<0.0001). Safety findings were consistent with previous clinical experience. Mirum plans a U.S. sNDA submission in the first half of 2027 based on these results.

• Primary Endpoint Achievement: The Phase 3 EXPAND study successfully met its primary endpoint, demonstrating a statistically significant improvement in cholestatic pruritus. Pediatric patients treated with maralixibat experienced a mean 1.81-point improvement from baseline in average worst-daily ItchRO(Obs) severity score during Weeks 13-20, significantly better than the 0.83-point improvement observed in the placebo group, with a p-value of 0.0004.
• Significant Reduction in Serum Bile Acids and Biliary Atresia Subgroup Efficacy: Maralixibat treatment led to a substantial 70.1% reduction from baseline in serum bile acids (sBA) across the overall population, compared to a mere 3.5% for placebo (p<0001). Furthermore, in the prespecified subgroup of patients with biliary atresia and a native liver, maralixibat also showed statistically significant improvements in pruritus (p=0.0002) and sBA reduction (p<0.0001).
• Consistent Safety Profile and Regulatory Path Forward: The safety profile of maralixibat in the EXPAND study was consistent with prior clinical experience, with no new safety signals identified. Based on these positive topline results, Mirum Pharmaceuticals intends to submit a supplemental New Drug Application (sNDA) in the United States during the first half of 2027, aiming to expand the approved indications for LIVMARLI to include these ultra-rare cholestatic liver diseases.

Addressing the Unmet Need in Cholestatic Pruritus

Cholestatic pruritus in ultra-rare liver diseases remains a significant therapeutic challenge, with current treatment options offering incomplete relief and limited evidence bases across disease subtypes. The stepwise management framework recommended by international societies — beginning with cholestyramine, followed by rifampicin, naltrexone, and sertraline — was developed largely for broader cholestatic conditions and does not fully address the complexity of ultra-rare presentations such as progressive familial intrahepatic cholestasis (PFIC) subtypes or biliary atresia.

• Absence of specific treatments for certain disease subtypes: No approved pharmacological therapies exist specifically for cholestatic pruritus in biliary atresia. In PFIC, response to ileal bile acid transporter (IBAT) inhibitors such as maralixibat is subtype-dependent: in the INDIGO study, serum bile acid response criteria were met in 7 of 19 patients with non-truncating BSEP mutations, while no patients with FIC1 deficiency or truncating BSEP deficiency met responder criteria.

• Refractory pruritus and reliance on surgical intervention: A substantial proportion of patients with ultra-rare cholestatic diseases do not respond adequately to conventional pharmacotherapy. In the ICONIC phase 2b study of maralixibat in Alagille syndrome, participants switched to placebo during the randomised withdrawal period experienced significant increases in serum bile acids (94 μmol/L; 95% CI 23 to 164) and pruritus (1.7 points; 95% CI 1.2 to 2.2), underscoring disease burden upon treatment discontinuation. Surgical options — including biliary diversion and liver transplantation — remain necessary for refractory cases, with liver transplantation reserved for intractable pruritus when all other options are exhausted.

• Poorly understood pathophysiology limiting targeted therapy development: The underlying mechanism of cholestatic pruritus remains incompletely elucidated. Although multiple mediators have been identified — including bile salts, opioids, steroids, and lysophosphatidic acid (LPA) — none are considered definitive key mediators. Only LPA and its synthesising enzyme autotaxin (ATX) appear to consistently correlate with symptom intensity, leaving multiple potential targets, especially within the ATX-LPA axis, pharmacologically unexplored.

• Heterogeneity across rare PFIC subtypes complicates generalisation of evidence: Real-world data on odevixibat in PFIC demonstrated that a serum bile acid level above 333.5 μmol/L increased the risk of non-response by 17-fold (p <0.001), highlighting that disease severity and subtype substantially influence treatment outcomes. Evidence in rarer PFIC subtypes (e.g., PFIC-4, PFIC-5, PFIC-6, PFIC-9) remains limited to case-level reports, with no large-scale trials available.

• Limitations in meta-analytic evidence for IBAT inhibitors: A meta-analysis of four randomised controlled trials of IBAT inhibitors in Alagille syndrome (138 children; mean age 6.1 years) identified heterogeneity in pruritus measurement instruments and dosing regimens, short follow-up periods of 24 weeks or less, and the use of non-interchangeable pruritus instruments across trials requiring standardised mean difference pooling — all of which preclude direct between-drug comparisons and limit the certainty of evidence.

• No approved or effective treatments for cholestatic fatigue: While pruritus is the most treatment-responsive complication of chronic cholestasis, fatigue — another common and debilitating complication — has no specific approved treatments, compounding the overall disease burden in patients with chronic cholestatic liver disease.

EXPAND Study Design and Positive Maralixibat Results

Several randomized and open-label trials have evaluated ileal bile acid transporter inhibitors (IBATIs) — primarily maralixibat and odevixibat — for cholestatic pruritus across ultra-rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and related disorders. The trials vary in phase, design, and pruritus assessment instruments, but share core endpoints around serum bile acid (sBA) reduction and validated pruritus scoring. Notably, biliary atresia patients were included in the phase 2 odevixibat study but have not been a primary population in dedicated IBAT pruritus trials.

Maralixibat's Expanding Role in Cholestatic Liver Diseases

Beyond its established role in paediatric cholestatic pruritus, maralixibat has been investigated across a broader range of cholestatic liver diseases in adults and children, with trial designs spanning open-label pilot studies and randomised placebo-controlled phases. The evidence base reflects an expanding clinical programme targeting bile acid dysregulation across multiple disease contexts.

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Reshaping the Cholestatic Pruritus Treatment Landscape

The regulatory approval of ileal bile acid transporter (IBAT) inhibitors has fundamentally reoriented the treatment paradigm for cholestatic pruritus in ultra-rare cholestatic liver diseases. Odevixibat (Bylvay) received FDA approval on July 20, 2021, for the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis (PFIC), based on a 24-week randomized, double-blind, placebo-controlled trial in 62 pediatric subjects with PFIC type 1 or type 2. In that trial, the mean percentage of observer-reported outcome (ObsRO) assessments scored as 0 or 1 was 35.4% and 30.1% for the 40 mcg/kg/day and 120 mcg/kg/day odevixibat arms, respectively, compared to 13.2% for placebo. Maralixibat, a selective apical sodium-dependent bile acid transport inhibitor, has similarly demonstrated durable efficacy across multiple indications. In the Phase 3 MARCH-PFIC trial, maralixibat produced a least-squares mean change from baseline in morning ItchRO(Obs) of -1.7 (95% CI -2.3 to -1.2) versus -0.6 (-1.1 to -0.1) for placebo in the BSEP cohort, a significant between-group difference of -1.1 (95% CI -1.8 to -0.3; p=0.0063), alongside a significant reduction in total serum bile acids of -187 μmol/L (95% CI -293 to -80; p=0.0013). In Alagille syndrome (ALGS), the Phase 3 ASSERT trial of odevixibat demonstrated a difference in least-squares mean change in scratching score of -0.9 (95% CI -1.4 to -0.3; p=0.0024) versus placebo, with serum bile acid reductions of -113 μmol/L (95% CI -179 to -47; p=0.0012). A meta-analysis of four randomized placebo-controlled trials in 138 children with ALGS confirmed that IBATIs reduced pruritus severity (SMD -1.00; 95% CI -1.64 to -0.35), lowered serum bile acid levels (MD -91.09 µmol/L; 95% CI -136.11 to -46.06; P <.0001), and improved PedsQL scores (MD 10.13 points; 95% CI 4.88 to 15.39).

Beyond pivotal trials, the evidence base has expanded to encompass rarer PFIC subtypes and novel disease contexts. In TJP2 deficiency (PFIC-4), a case series of five children treated with odevixibat showed serum bile acid reduction from a mean of 244 (±125) to 38 (±34) µmol/L (p=0.007), with pruritus improvements in all patients. A case report in PFIC9, caused by a homozygous ZFYVE19 mutation, documented a reduction in serum bile acids from 458 to 71 μmol/L and a Caregiver Global Impression of Severity score reduction from 5 to 1 following odevixibat. In biliary atresia, preclinical evidence from murine models of sclerosing cholangitis demonstrated that IBAT inhibitor-mediated reduction of hepatic bile acid concentration promoted hepatic regulatory T cell responses, leading to diminished liver injury and fibrosis, providing mechanistic rationale for clinical investigation in this population. An indirect treatment comparison of maralixibat and odevixibat in PFIC, anchored by placebo arms of MARCH-PFIC and PEDFIC-1, indicated that maralixibat was significantly more efficacious than odevixibat 120 µg/kg in achieving serum bile acid response, with an estimated treatment difference of 32.3% (95% CI, 1.1% to 63.4%; P=0.043), though safety profiles were broadly comparable. In ALGS, a separate indirect treatment comparison using ASSERT/ASSERT-EXT and ICONIC data suggested odevixibat was associated with significantly greater improvements in overall PedsQL scores (mean difference: 14.64; 95% CI: 5.70–23.58) and significantly lower rates of gastrointestinal adverse events (OR: 0.22; 95% CI: 0.06–0.87) versus maralixibat.

The evolution of the treatment landscape has also been shaped by long-term outcomes data and the repositioning of surgical biliary diversion. A comparison of 6-year outcomes from maralixibat trials (84 ALGS patients) against a harmonized natural history cohort from the Global Alagille Alliance (GALA; 469 aligned participants) demonstrated significantly better event-free survival in the maralixibat cohort (HR, 0.305; 95% CI, 0.189–0.491; p <0.0001), where events were defined as manifestations of portal hypertension, surgical biliary diversion, liver transplant, or death. In the INDIGO Phase 2 study, all seven serum bile acid responders among patients with non-truncating BSEP deficiency remained liver transplant-free after more than 5 years of maralixibat treatment. These data collectively position IBAT inhibitors not merely as antipruritic agents but as potential modifiers of disease trajectory. Surgical biliary diversion, while still practiced — including partial external biliary diversion and internal Roux-en-Y cholecystocolostomy — is increasingly being evaluated in the context of pharmacological alternatives, with case reports documenting successful maralixibat use before and after reversal of surgical biliary diversion. Conventional therapies including ursodeoxycholic acid, cholestyramine, rifampicin, and opioid antagonists continue to be used, but a systematic literature review identified a lack of consistent and reproducible evidence for their efficacy in cholestatic pruritus, underscoring the clinical significance of the IBAT inhibitor approvals in reshaping standard of care for these ultra-rare diseases.

Maralixibat's Breakthrough in Biliary Atresia: Reshaping Cholestatic Care

The recent positive topline results for maralixibat in the Phase 3 EXPAND study for cholestatic pruritus in biliary atresia mark a pivotal moment for patients and clinicians grappling with this devastating pediatric liver disease. Biliary atresia is characterized by blocked bile ducts, leading to bile acid accumulation, severe pruritus, and progressive liver damage, often culminating in the need for liver transplantation. Current management, primarily surgical intervention with Kasai portoenterostomy, frequently falls short in preventing disease progression, leaving a significant unmet need for effective medical therapies.

Maralixibat, an ileal bile acid transporter (IBAT) inhibitor, works by interrupting the enterohepatic circulation of bile acids, thereby reducing their toxic levels in the liver and alleviating symptoms like pruritus. This mechanism has already demonstrated durable and clinically meaningful improvements in other cholestatic conditions such as Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), where it has shown benefits in pruritus, serum bile acid reduction, and even native liver survival in specific PFIC subtypes. The EXPAND study's success in biliary atresia, showing significant reductions in pruritus and serum bile acids, suggests that maralixibat could offer a much-needed non-surgical option, potentially delaying or even preventing the need for liver transplantation and profoundly improving the quality of life for these young patients.

However, as with any novel therapy, considerations remain. While generally well-tolerated, IBAT inhibitors are known to cause gastrointestinal side effects, such as diarrhea, and transient elevations in liver enzymes like ALT, which require careful monitoring. Furthermore, while the immediate symptomatic and biochemical improvements are clear, the long-term impact on native liver survival in biliary atresia, a disease with a complex natural history, will be crucial to fully understand. The competitive landscape also features other IBAT inhibitors, and while maralixibat has shown favorable comparisons in some contexts, others suggest potential advantages for competitors in areas like tolerability or quality of life in specific indications. Despite these considerations, the prospect of a targeted pharmacological treatment for cholestatic pruritus in biliary atresia represents a significant step forward, offering hope for a new standard of care.