ABSTRACT
Background
Alagille syndrome (ALGS) is a multisystem cholestatic disorder. Maralixibat is approved for the treatment of cholestatic pruritus in ALGS with limited data in adults.
Methods
Participants were included if they received ≥ 2 doses of maralixibat at age ≥ 16 years in one of the three previously published maralixibat ALGS clinical trials.
Results
Eleven initiated treatment < 16 years old (median age, 13.0) with a median follow‐up of 4.1 years. Three participants began maralixibat at ≥ 16 years old, with a median follow‐up of 3.8 years. Participants starting maralixibat at age < 16 had minimal‐to‐no itch (change from baseline [CFB]: −1.8; p = 0.002) persisting throughout the study. Serum bile acids (sBA) decreased (CFB: 29 μmol/L; p = 0.03), persisting throughout the study. Participants starting maralixibat ≥ 16 years old had pruritus improvements (CFB: −2.8, −0.6, −1.0). One had a large decrease in sBA (CFB: −112 μmol/L), and two had small increases (CFB: 8, 11 μmol/L). Maralixibat was well tolerated.
Conclusion
Participants receiving maralixibat in adolescence demonstrated improvements in pruritus and sBA, which persisted through young adulthood.
Keywords: Alagille syndrome, cholestatic pruritus, maralixibat, serum bile acids
Summary.
Alagille syndrome (ALGS) is a rare disorder that affects multiple systems in the body, particularly causing itching due to liver problems.
Maralixibat is a treatment that is approved for itching in ALGS and has been studied primarily in children, although some patients have received maralixibat through adolescence and into young adulthood.
This current analysis reviewed the effectiveness and safety of maralixibat in all participants who were in a maralixibat clinical trial that received ≥ 2 doses of maralixibat when they were ≥ 16 years old.
The participants experienced significant and lasting relief from itching and had lower levels of bile acids over several years.
Overall, maralixibat was well tolerated by participants.
In conclusion, maralixibat is effective for managing symptoms of ALGS, providing relief from itching and lowering bile acid levels from adolescence continuing into young adulthood.
Abbreviations
- AE
adverse event
- ALGS
Alagille syndrome
- GGT
gamma‐glutamyl transferase
- GI
gastrointestinal
- IBATi
ileal bile acid transporter inhibitor
- ItchRO(Obs)
Itch‐Reported Outcome (Observed)
- LT
liver transplant
- MRX
maralixibat
- Q
quartile
- sBA
serum bile acid
- TEAE
treatment‐emergent adverse event
1. Introduction
Alagille syndrome (ALGS) is an inherited multisystem disorder characterised by cholestatic liver disease secondary to bile duct paucity. Other notable features with variable expression include pulmonary artery stenosis, characteristic facies, posterior embryotoxon, butterfly vertebra, and vascular and renal anomalies. One of the most distressing complications secondary to chronic cholestasis is unremitting pruritus, which is reported in up to 88% of children with ALGS [1]. Serum bile acids (sBA) have been implicated as key mediators of cholestatic itch, although the exact mechanisms underlying this relationship have not been fully elucidated. Pruritus in ALGS is often refractory to conventional antipruritic therapies, and surgical biliary diversion has shown limited efficacy [2]. Moreover, pruritus is a leading indication for liver transplant (LT) [3]. Meanwhile, 24%–40% of patients with ALGS reach adulthood with their native liver and may require treatment for pruritus [3, 4].
Maralixibat is an inhibitor of the ileal bile acid transporter (IBATi), a key molecule in the enterohepatic circulation, which reabsorbs bile acids from the small intestine. In clinical trials of children with ALGS, treatment with maralixibat led to a statistically and clinically significant reduction in both pruritus and sBA [5, 6, 7]. Maralixibat is the first pharmacologic therapy approved by the US Food and Drug Administration (FDA) and the European Medical Agency (EMA) for the treatment of cholestatic pruritus in patients with ALGS ≥ 3 and ≥ 2 months of age, respectively.
Although clinical trials of IBATi have included adolescents, the majority of participants in these trials are aged < 12 years. Here, the efficacy and safety of maralixibat from three previously published clinical trials are evaluated in participants with ALGS who used maralixibat as adolescents (age ≥ 16) [5, 6, 7].
2. Patients and Methods
2.1. Study Design
This analysis integrates patient data from three clinical trials of maralixibat (ITCH [NCT02057692], IMAGO [NCT01903460], and ICONIC [NCT02160782]) that have been described elsewhere [5, 6, 7]. Participants who received ≥ 2 doses of maralixibat at age ≥ 16 and had a mean daily Itch‐Reported Outcome (Observer) (ItchRO[Obs]) score of ≥ 2 for 2 consecutive weeks were included. During the trials, participants received the daily dose appropriate for their weight (up to 285 μg/kg/day), with a maximum dose of 28.5 mg/day.
All participants or guardians provided written informed consent. The trial protocols were approved by the ethics board at each centre and conducted according to the Declaration of Helsinki.
2.2. Study Variables
The analysis was conducted separately for two age groups based on when maralixibat was initiated. One cohort started maralixibat before age 16 years, and comparisons were made at: (1) baseline, before starting maralixibat; (2) pre‐age 16, value immediately before age 16 years; (3) post‐age 16, value immediately after age 16 years; and (4) end of observation, last trial value. The second cohort started maralixibat after age 16 years, and comparisons were made between baseline (before starting maralixibat) and the end of observation (last trial value). Pruritus was assessed by participants and/or their caregivers with the ItchRO(Obs) [8]. This scale ranges from 0 to 4, with a ≥ 1‐point reduction considered clinically meaningful. Xanthomas were evaluated using the Clinical Xanthoma Scale. Treatment‐emergent adverse events (TEAEs) were defined as any adverse event (AE) that manifested on the date of the first maralixibat dose and during treatment.
2.3. Statistical Analysis
Quantitative variables are presented as medians (quartile 1 [Q1], quartile 3 [Q3]), and qualitative variables are reported as frequencies with percentages. Wilcoxon rank‐sum tests were used to compare changes at different time points. For sBA, the average of the last two records before and after age 16 and at end of the study were reported.
3. Results
3.1. Baseline Characteristics
Fourteen adolescents with ALGS participated in the maralixibat clinical development program (ITCH/IMAGINE II [LUM001‐301/305]: n = 6; IMAGO/IMAGINE [LUM001‐302/303]: n = 4; and ICONIC [LUM001‐304]: n = 4) with baseline characteristics reported in Table 1. Eleven participants (45% male) began treatment with maralixibat before age 16 (median age 13.0; Q1, Q3: 12.0, 15.0) years. In this group, the median duration of therapy was 4.1 (Q1, Q3: 1.5, 5.9) years, with the oldest participant taking maralixibat up to age 21. Three participants (67% male) began maralixibat treatment at age ≥ 16 and were followed for a median of 3.8 (min, max: 1.6, 4.0) years. No participants were reported to have xanthomas during the course of the study.
TABLE 1.
Key demographics and baseline characteristics (N = 14).
| Participants aged < 16 years at MRX initiation | Participants aged ≥ 16 years at MRX initiation | |
|---|---|---|
| n | 11 | 3 |
| Male, n (%) | 5 (45.5) | 2 (66.7) |
| Median age, years (Q1, Q3) | 13.0 (12.0, 15.0) | 16.3 (min, max: 16.0, 17.0) |
| Height Z‐score (Q1, Q3) | −1.3 (−3.0, −0.6) | −1.1 (min, max: −1.5, −0.4) |
| Weight Z‐score (Q1, Q3) | −1.9 (−2.5, −1.3) | −1.3 (min, max: −1.7, −0.2) |
| Pruritus, ItchRO(Obs) (Q1, Q3) | 2.4 (1.8, 3.0) | 2.8 (min, max: 2.6, 4.0) |
| Baseline laboratory values | ||
| Total sBA, μmol/L (Q1, Q3) | 60 (31, 181) | 29 (min, max: 21, 196) |
| Total bilirubin, mg/dL (Q1, Q3) | 1.2 (0.7, 2.1) | 1.0 (min, max: 0.5, 1.9) |
| Direct bilirubin, mg/dL (Q1, Q3) | 0.8 (0.4, 1.1) | 0.5 (min, max: 0.4, 2.2) |
| ALT, U/L (Q1, Q3) | 124 (54, 214) | 95 (min, max: 92, 130) |
| GGT, U/L (Q1, Q3) | 267 (n = 7) (147, 928) | 964 (min, max: 178, 1143) |
| Cholesterol, mg/dL (Q1, Q3) | 280 (237, 361) | 206 (min, max: 158, 281) |
| Platelet count, 109/L (Q1, Q3) | 253 (208, 296) | 176 (min, max: 73, 372) |
Note: Quantitative variables are presented as medians (quartile 1 [Q1], quartile 3 [Q3]), unless otherwise specified.
Abbreviations: ALT, alanine aminotransferase; GGT, gamma‐glutamyl transferase; ItchRO(Obs), Itch‐Reported Outcome (Observer); MRX, maralixibat; sBA, serum bile acid.
3.2. Pruritus
Among the 11 participants who began maralixibat before age 16, 9 had ItchRO(Obs) scores available for all time points for analysis. At baseline, their median ItchRO(Obs) score was 2.4 (Q1, Q3: 1.3, 3.5) and significantly decreased at their pre‐age 16 visit to 0.6 (Q1, Q3: 0.0, 2.2) (Δ: −1.8; p = 0.002), indicating minimal to no itch (Figure 1). The treatment response was robust and durable, with reductions in ItchRO(Obs) maintained throughout treatment and no significant differences from pre‐ to post‐age 16 (Δ: −0.2; p = 0.20) or from post‐age 16 to the end of observation (Δ: 0.2; p = 0.30). Among the three participants who started maralixibat at age ≥ 16, all had improvements in pruritus from baseline to the end of observation (Δ: −2.8, −0.6, and −1.0).
FIGURE 1.
Time courses for changes in (A) ItchRO(Obs) and (B) sBA for participants who initiated treatment with maralixibat at age < 16 (n = 11) and ≥ 16 years (n = 3). *Of 11 participants, 9 had ItchRO(Obs) scores available for all time points and were included in this analysis. †Average of the last 2 records prior to turning 16 years of age. ‡Average of the first 2 records after turning 16 years of age. §Average of the last 2 records in LUM001‐303/304/305. Error bars represent SE. ItchRO(Obs), Itch‐Reported Outcome (Observer); MRX, maralixibat; sBA, serum bile acid.
3.3. Laboratory Findings
Among the 11 participants who began maralixibat treatment before age 16, sBA data were available for all time points. At baseline, median sBA was 60.4 (Q1, Q3: 30.9, 181.1) μmol/L and significantly decreased at the pre‐age 16 years visit to 31.4 (Q1, Q3: 11.3, 95.6) μmol/L (p = 0.03; Figure 1). This reduction was durable and continued throughout treatment, with significant differences in sBA from pre‐ to post‐age 16 years (Δ: −29.7; p < 0.001) and a nonsignificant, numeric reduction from post‐age 16 years to the end of observation (Δ: −7.1; p = 0.10). Among the three participants who started maralixibat at age ≥ 16, sBA dramatically decreased in one participant (Δ: −112.0 μmol/L), with small increases in sBA in the other participants (Δ: 8.0 and 11.0 μmol/L; Figure 1). Median values for total and direct bilirubin and other assessments of hepatic function remain stable from baseline through the end of observation for either group. Thrombocytopenia was present in one participant (7%, n = 1/14) at baseline (platelets 73.0 × 109/L) who started maralixibat after age 16 and remained stable throughout the study.
3.4. Long‐Term Outcomes
No deaths were reported. One LT occurred in one participant who initiated maralixibat before age 16 due to hepatocellular carcinoma (HCC). This event occurred 4.3 years after initiating maralixibat and was determined to be unrelated to treatment by investigators. There were no reports of disease progression, including portal hypertension or metabolic bone disease.
3.5. Safety Profile
During the clinical trials, TEAEs occurred in all participants receiving maralixibat (Table S1), with the majority (78.5%) classified as grade 1 or 2. Gastrointestinal (GI) TEAEs were the most frequent, including diarrhoea (57.1%) and abdominal pain (50.0%). Events were generally mild or moderate in severity and primarily occurred during dose escalation in the first few months. One treatment‐related AE of increased pruritus (grade ≥ 3) was reported and resolved without dose modification or clinical sequelae. There were no study‐drug discontinuations due to AEs and no apparent drug‐related serious AEs. Overall, maralixibat was considered to be well tolerated in these participants.
4. Discussion
In this analysis, the efficacy and safety of maralixibat were evaluated in adolescents with ALGS, an underreported age group in previous IBATi therapy research. For those who started maralixibat in early adolescence (before age 16), a clinically and statistically meaningful improvement in pruritus and a statistically significant reduction in sBA were achieved and persisted into late adolescence or adulthood. Those who started later in adolescence (after age 16) also showed a robust and durable improvement in pruritus like other children from clinical trials.
The safety profile of maralixibat among adolescents is favourable and consistent with previously reported paediatric data. As IBATi divert bile acids, GI AEs, including diarrhoea and abdominal pain, were the most common TEAEs. Most importantly, no participants discontinued maralixibat due to TEAEs. These findings were similar to results from those participants who were of younger age (≤ 13 years of age) in the pivotal ICONIC study, which reported GI events in 71% of ALGS participants during the open‐label period. Moreover, the frequency of GI events is comparable to a recent study of maralixibat in adults with primary sclerosing cholangitis, a biliary disorder with historically high rates of inflammatory bowel disease [9].
During the study period, no deaths were reported, and only one participant underwent LT with the indication being HCC, a rare clinical sequelae of ALGS reported in < 1% of cases [3, 10]. Despite the rarity of HCC in ALGS, these data provide support for heightened awareness and ongoing surveillance of HCC throughout adolescence and adulthood [11]. During the trials, there were no reports of portal hypertension, including varices or ascites requiring treatment with diuretics. A recent study of 293 children with ALGS reported a second wave of hepatic disease, specifically events of clinically evident portal hypertension, emerging in late childhood [4]. The low frequency of liver‐related events in our cohort may be due to decreases in sBA leading to a reduction in intrahepatic bile acid accumulation and consequent liver damage. However, it should be noted that a control group was not included in this analysis, inhibiting definitive conclusions. While the low frequency of liver‐related events could also be due to potentially milder disease in these specific participants allowing them to survive into adolescence and young adulthood, that is most likely not the case given the high levels of sBA and pruritus observed at baseline. There is, however, additional evidence demonstrating a link between maralixibat and improved clinical outcomes in ALGS that was shown in a landmark study by the GALA Study Group [12]. In this study, Hansen et al. demonstrated improved event‐free survival in children with ALGS treated with maralixibat compared with a real‐world natural history cohort.
There are a few limitations that warrant discussion. The number of participants in each age group is relatively small, possibly attributed to the high rate of LT among individuals with ALGS during early childhood. Despite pruritus, participants were generally healthy at baseline without evidence of cirrhosis, so it may be difficult to extrapolate findings to adolescents with more advanced liver disease. In addition, this analysis is limited in that it does not incorporate a placebo comparison but rather makes intra‐individual comparisons for participants while on therapy, and, as such, improvements could theoretically be part of individual trajectory rather than the benefit of the drug. Despite these limitations, the current research demonstrates a substantial and sustained improvement in pruritus and sBA levels among adolescents and young adults with ALGS undergoing maralixibat treatment.
5. Conclusion
This analysis extends earlier observations from prior analyses in children that maralixibat is effective, durable, and well tolerated in patients with ALGS. Specifically, in the subgroup of participants who started maralixibat prior to or around 16 years of age, the clinical effect of maralixibat persisted beyond age 16 years in those participants. Given that pharmacologic interruption of the enterohepatic circulation improves pruritus and sBA, it is plausible that similar benefits may be achieved for other complications of chronic cholestasis. These observations support the potential for maralixibat to have a positive impact on adolescents with ALGS who survive with their native livers into adulthood.
Author Contributions
All authors contributed to the analysis, writing, review, and decision to submit the manuscript.
Ethics Statement
The trial protocols were approved by the ethics board at each centre and conducted according to the Declaration of Helsinki.
Consent
All participants or guardians provided written informed consent.
Conflicts of Interest
G.H. has nothing to disclose. S.M.V. reports consulting fees for Mirum Pharmaceuticals Inc. D.B.M., M.B., and P.V. are employees of and shareholders in Mirum Pharmaceuticals Inc. B.M.K. is a consultant for Mirum Pharmaceuticals Inc., Ipsen, and Audentes and received grants from Mirum Pharmaceuticals Inc., and Ipsen.
Supporting information
Appendix S1
Acknowledgements
The authors would like to thank the patients and families involved in the maralixibat clinical development program to date. Maralixibat is owned by Mirum Pharmaceuticals Inc. This analysis was funded by Mirum Pharmaceuticals Inc.
Handling Editor: Alessio Aghemo
Funding: This study and the clinical trials upon which it is based were funded by Mirum Pharmaceuticals Inc.
Data Availability Statement
Beginning 6 months and ending 5 years after publication, de‐identified participant data for data meta‐analysis might be made available to investigators whose proposed use of the data has been approved by a review committee, including the primary authors and the study funder. The study protocol will also be available via weblink. Proposals should be directed to medinfo@mirumpharma.com. Before being granted access, data requesters will be required to sign a data access agreement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1
Data Availability Statement
Beginning 6 months and ending 5 years after publication, de‐identified participant data for data meta‐analysis might be made available to investigators whose proposed use of the data has been approved by a review committee, including the primary authors and the study funder. The study protocol will also be available via weblink. Proposals should be directed to medinfo@mirumpharma.com. Before being granted access, data requesters will be required to sign a data access agreement.