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H-O029 - MARALIXIBAT IMPROVES CHOLESTATIC PRURITUS AND BILE ACIDS IN CHILDREN WITH FIC1: DATA FROM THE MARCH-PFIC TRIAL (ID 468)
Abstract
Objectives and Study
Familial Intrahepatic Cholestasis type 1 (FIC1) disease is a form of Progressive Familial Intrahepatic Cholestasis (PFIC), a group of autosomal recessive liver disorders of impaired bile acid transport leading to intrahepatic cholestasis, pruritus, and liver failure. Nearly half of FIC1 patients will require a liver transplant, but in many instances, transplant is not curative. Maralixibat (MRX), an ileal bile acid transporter inhibitor, significantly improved pruritus, serum bile acids (sBA), bilirubin, and growth in the All-PFIC cohort from the MARCH-PFIC Phase 3 trial, which used a higher dose of MRX than previously studied. Here we report on results from the FIC1 subgroup.
Methods
Participants from MARCH-PFIC with biallelic disease-causing variations in the ATP8B1 gene received MRX 570 µg/kg BID or placebo for 26 weeks. Key efficacy endpoints included improvements in pruritus, sBA, and bilirubin.
Results
13 FIC1 participants were randomized (n=7 maralixibat; n=6 placebo). Groups were well-balanced with respect to Baseline pruritus score (3.2 vs 3.4 on 0-4 ItchRO[Obs] score) and sBA (206 µmol/L for both). Significant changes from Baseline (CFB) were observed in ItchRO(Obs) response (p=0.0186) and sBA reduction (p=0.0298) in the maralixibat group, whereas no significant CFB were seen in placebo (Table). Three of seven MRX participants achieved sBA response predictive of transplant-free survival vs 0 in placebo. Numerical decreases in total and direct bilirubin (-2.1, -1.7 mg/dL) were observed in maralixibat participants, with increases in placebo. Treatment-emergent adverse events were reported in all participants; no serious events reported in MRX participants. Diarrhea was reported in 4 MRX and 2 placebo, all mild in severity. No participants discontinued treatment.
Conclusions
In participants with FIC1 disease, MRX was well-tolerated and associated with improvements in the efficacy endpoints of pruritus and sBA whereas no significant changes were observed in placebo. Decreased serum bilirubin levels may suggest improvement in liver health.
H-O021 - ODEVIXIBAT TREATMENT INDUCES BILIARY BILE ACID SECRETION IN RESPONSIVE PATIENTS WITH BILE SALT EXPORT PUMP DEFICIENCY (PFIC2) (ID 179)
Abstract
Objectives and Study
Odevixibat blocks the ileal bile acid transporter and reduces serum bile acid (sBA) concentration in patients with progressive familial intrahepatic cholestasis (PFIC). To further understand the anti-cholestatic effect of odevixibat, we evaluated the sBA composition in patients with bile salt export pump (BSEP) deficiency (PFIC2) categorized by their sBA response to odevixibat.
Methods
PEDFIC 1 (NCT03566238) eligibility criteria included elevated sBAs at screening; concomitant ursodeoxycholate (UDCA) was allowed if the patient was on a stable dose. Two categories of PFIC2 patients were defined: responders (R) had a reduction of their sBA concentration by ≥70% from baseline to end of treatment (EOT) or a sBA concentration of ≤70 μmol/L at EOT. Nonresponders (NR) did not meet these criteria. After 24 weeks of treatment, sBAs were quantified by liquid chromatography−tandem mass spectrometry. We quantified unconjugated BAs, cholate (CA), chenodeoxycholate (CDCA), UDCA, deoxycholate (DCA), lithocholate (LCA), and total glycine- and taurine-conjugated BAs. Composition was expressed as a percentage of total sBAs, subtracting UDCA.
Results
Thirty odevixibat-treated patients with PFIC2 (15 R; 15 NR) were included in the analysis. The percentage of unconjugated sBAs was ~70-fold higher in Rs vs NRs (P<0.001; Table). The secondary sBAs DCA and LCA were virtually absent in both Rs and NRs (P=0.19; Table). Rs had a 66% lower CA/CDCA ratio and a >2-fold higher glycine-conjugated/taurine-conjugated BA ratio compared with NRs (P=0.002 and P<0.001, respectively; Table), reaching corresponding values of healthy children.
Conclusions
sBA responsiveness to odevixibat treatment in patients with PFIC2 is not only defined by a decrease in sBA concentration, but also by alterations in sBA composition. Exclusively in Rs, odevixibat treatment is associated with a strongly increased relative contribution of unconjugated BAs. Since unconjugated BAs originate from deconjugation of biliary BAs by the intestinal microbiome, our data indicate that odevixibat induces biliary BA secretion in treatment-responsive patients with PFIC2.
H-O023 - EFFICACY AND SAFETY OF ODEVIXIBAT IN PATIENTS WITH ALAGILLE SYNDROME: INTERIM RESULTS FROM THE OPEN-LABEL, PHASE 3 ASSERT-EXT STUDY (ID 361)
Abstract
Objectives and Study
In the 24-week, placebo-controlled, phase 3 ASSERT study (NCT04674761), odevixibat, an ileal bile acid transporter inhibitor, significantly improved pruritus and sleep disturbance and reduced bile acids (BAs) in patients with Alagille syndrome (ALGS). The ongoing, phase 3, open-label extension study ASSERT-EXT (NCT05035030) further evaluates efficacy and safety of odevixibat in patients with ALGS.
Methods
Patients could enter ASSERT-EXT after completing ASSERT; all patients in ASSERT-EXT received odevixibat 120 μg/kg/day. Two groups were analysed up to an interim cut-off date of 09 September 2022: treatment-naive patients (received placebo in ASSERT; ie, “placebo-odevixibat”) and patients who received odevixibat in ASSERT (ie, “odevixibat-odevixibat”). Outcomes evaluated included pruritus, serum BAs, sleep, and treatment-emergent adverse events (TEAEs).
Results
At the cut-off date, 49 patients had been treated in ASSERT-EXT (placebo-odevixibat: n=17; odevixibat-odevixibat: n=32). Patients in the odevixibat-odevixibat group entered ASSERT-EXT with improved pruritus, BAs, and sleep; these parameters showed uniform and sustained improvement with longer treatment (Table). Patients in the placebo-odevixibat group had mean reductions in pruritus and BAs (Table); a pruritus reduction ≥1-point from baseline was achieved in 70% of patients in the placebo-odevixibat group at weeks 9–12 of ASSERT-EXT. Both groups had mean reductions in percentage of days needing help falling asleep or soothing (Table). Most TEAEs were mild to moderate in severity; serious TEAEs were reported in 2/49 patients (4%). Incidence of treatment-emergent and drug-related diarrhoea was 16% and 4%. No drug-related serious TEAEs or TEAEs leading to discontinuation or dose reduction were reported.
Conclusions
Consistent with results from ASSERT, an interim analysis of ASSERT-EXT data showed that treatment-naïve patients with ALGS had rapid improvements in pruritus, sleep, and BAs with odevixibat; patients previously treated with odevixibat showed sustained improvements in these outcomes with continued treatment. Odevixibat treatment for ≥24 weeks in patients with ALGS was well tolerated.
H-O003 - REAL-LIFE EXPERIENCE OF TREATMENT WITH ODEVIXIBAT IN PFIC PATIENTS: AN ITALIAN STUDY BY THE SIGENP LIVER DISEASE WORKING GROUP (ID 565)
Abstract
Objectives and Study
Odevixibat has been recently approved for the treatment of children with progressive familial intrahepatic cholestasis (PFIC). We aim to present our “real life experience” of odevixibat use in children to add information on response to treatment by different PFIC subtypes.
Methods
multicentre study of PFIC patients treated with odevixibat in 2021-2022 outside clinical trials. End-points were: reduction in serum bile acids (sBA) ≥70% from baseline (or <70 micromol/L) at last follow-up; any improvement in pruritus scale. Only patients having a follow up ≥3 months were included in the analysis.
Results
23 patients [median age at diagnosis 1.7 years (0.8-4.5), M/F=11/12], from 11 centres, with a genetically confirmed diagnosis of PFIC-1 (n=3; 1 with recurrent episodes of cholestasis), PFIC-2 (n=10), PFIC-3 (n=3), PFIC-4 (n=5), PFIC-5 (n=1), and PFIC-9 (n=1) received odevixibat. At baseline (median age 6.9 years, 5-12.1), all patients (100%) had high sBA levels, and in almost all cases (20/23, 87%), clinically relevant pruritus and sleep disturbances. Response to treatment was assessed in 21/23 patients (91%), 2 were excluded for short follow up. After a median of 170 days (138-230) of treatment, sBA response was recorded in 18/21 patients (86%) [median baseline value 267 (127-323) vs 44 (5-90) µmol/L; p<0.001]; reduction in sBA >70% was reported in 64% of patients. Improvements in pruritus and sleep disturbances were reported in 73% of patients. Three of 21 (14%) did not respond and discontinued the treatment. No serious adverse events were recorded.
Conclusions
treatment with odevixibat is effective and safe in reducing sBA levels and improve pruritus in patients with PFIC in a real life setting. Odevixibat treatment should be considered in patients with classic types of PFIC as well as in other rarer subtypes.
H-O010 - MARALIXIBAT IMPROVES XANTHOMAS AND HYPERCHOLESTEROLEMIA IN CHILDREN WITH ALAGILLE SYNDROME: AN INTEGRATED ANALYSIS FROM TWO CLINICAL TRIALS (ID 472)
Abstract
Objectives and Study
Unlike other causes of cholestasis, a unique manifestation of Alagille syndrome (ALGS) is xanthomas in one-quarter of patients and no approved medical therapies exist. As xanthomas have not been well-characterized, we evaluated their baseline characteristics, impact of maralixibat on xanthomas, and correlates of xanthoma reduction following treatment.
Methods
Data were obtained from the maralixibat ALGS program. Xanthomas were assessed using the Clinician Xanthoma Scale (CXS) with response defined as ≥1-point reduction in CXS (xanthomas at Baseline present) versus non-response as unchanged/worsened CXS.
Results
27 of 63 (43%) individuals had xanthomas at Baseline. At Baseline, higher CXS was associated with lower age (p=0.0284), higher total/direct bilirubin (p<0.0001; p<0.0001), higher sBA (p=0.0004), higher total cholesterol and LDL (p<0.0001; p=0.0556), lower HDL (p=0.0005), lower PedsQL social functioning (SF; p=0.0193), and lower physical functioning (PF, p=0.0367) (Table). With maralixibat, the proportion with no xanthomas (CXS 0) increased over 96 weeks, from 60% to 86%, while the proportion with moderate xanthomas (CXS 1-2) decreased from 33% to 9%, and the proportion with severe xanthomas (CXS 3-4) decreased from 9% to 6% (p=0.0039). Follow-up data to Week 96 were available for 35 individuals of which 14 (40%) had xanthomas at Baseline. From Baseline to Week 96, there was a decrease in total cholesterol (-57 mg/dL, p=0.0009) and LDL (-22 mg/dL, p=0.0041) and increase in HDL (14 mg/dL, p<0.0001). Of those with week 96 data, 10/14 (71%) were xanthoma-responders. Responders with QoL assessments (n=9) had improved PedsQL‑SF (20) and PedsQL-PF (15.4), whereas non-responders had little change in PedsQL-SF (1.2) and PedsQL-PF (3.1). At Week 48, xanthoma-responders vs non-responders had decreased total cholesterol (-189 mg/dL vs -11 mg/dL; p=0.0045).
Conclusions
At Baseline, increased xanthomas was associated with biomarkers of disease and QoL. Xanthomas improved following treatment with maralixibat over 96 weeks. Xanthoma reduction was associated with improved QoL and total cholesterol.
H-O008 - REAL-WORLD SAFETY EXPERIENCE IN PATIENTS WITH ALAGILLE SYNDROME TREATED WITH MARALIXIBAT (ID 463)
Abstract
Objectives and Study
Maralixibat (MRX) is an IBAT inhibitor that received a positive CHMP opinion for the treatment of cholestatic pruritus in ALGS patients ≥2 months of age. A global Expanded Access Program (EAP) facilitated access to MRX for patients with ALGS who could not participate in clinical trials. Rare disease clinical trials are often limited by narrowly selected populations, small sample sizes, and evaluation of treatment-emergent adverse events (TEAEs) that may not reflect real-word experience (RWE). We report on the safety profile from this EAP RWE of MRX.
Methods
Baseline characteristics and TEAEs were reported to a central database. All patients who received MRX through the EAP (with a target dose of 380 µg/kg PO daily) were included. TEAEs were defined as those occurring on or after the first dose of MRX and within 14 days from the last medication dose.
Results
37 patients enrolled in the EAP; median [Q1, Q3] age 6.7 [1, 27] years, weight 16 [7, 60] kg, and 20 (54%) males. Median duration of follow-up was 243 [52, 385] days. ≥1 TEAE occurred in 16 (43%) patients. Three patients (8%) experienced gastrointestinal treatment-related AEs which were mild in severity; no patient experienced fat soluble vitamin deficiency. There were three (8%) grade 3 TEAEs, two of which (viral infection and fever) were additionally labelled serious because they required hospitalization; the third patient with grade 3 TEAE had elevated liver enzymes that led to the only event of MRX discontinuation. Three patients (8%) required dose reduction for diarrhea (n=2), and incorrect initial dosing (n=1). One patient (3%) interrupted dosing for mild liver enzyme elevation (grade 1).
Conclusions
MRX is well-tolerated in patients with ALGS in the real-world setting. GI events, FSV deficiency, nor liver enzyme elevations are treatment limiting in this setting.
H-O042 - SIROLIMUS FOR TREATING CHRONIC AND STEROID-RESISTANT ALLOGRAFT REJECTION-RELATED FIBROSIS IN PEDIATRIC LIVER TRANSPLANTATION (ID 681)
Abstract
Objectives and Study
The aim of our study was to report the histological evolution of all pediatric LT patients with chronic rejection or steroid-resistant liver rejection with hepatic fibrosis treated with sirolimus.
Methods
This is a single-center retrospective observational study. Data were collected from all pediatric LT patients who received off-label treatment with sirolimus due to steroid-resistant rejection with fibrosis or chronic rejection between January 2002 and December 2021. Diagnosis of steroid-resistant liver rejection and chronic rejection was always performed by biopsy. Follow-up liver biopsies were routinely obtained from all LT patients with normal liver function tests at 2, 5, 10, 15 years after transplantation. Sirolimus was started when chronic rejection was diagnosed or when a steroid-resistant rejection with fibrosis (stage 2 or higher) were detected.
Results
During the study period, five patients received sirolimus because of chronic rejection and four because of steroid-resistant rejection. The median starting and last follow-up doses were: 1,5 mg/day (r: 0.8 - 3.0) and 2.0 mg/day (r: 1.2 - 3.0), respectively. Median follow-up time after the introduction of sirolimus was of 8.6 years (1.1-16.5). Fibrosis improvement was observed in 7 of out 9 patients (77.7%) at 12 months, with complete histological normalization in three of them. One of the two patients who had no improvement in their graft fibrosis at 12 months presented fibrosis resolution at 36 months biopsy. In all patients ductopenia improved at 12 months biopsy, with not ductal damage noted in three patients. Four additional patients presented ductopenia resolution at liver biopsy performed at 36 months post-sirolimus. Changes in Fibrosis, Rejection Activity Index and Ductopenia are shown in Figure 1.Although seven patients experienced side effects related to sirolimus, they were mild and self-limited
Conclusions
Sirolimus may be a safe and effective treatment for chronic and steroid-resistant rejection, and may improve allograft rejection-related fibrosis and ductal damage.