Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Mirum Pharmaceuticals International B.V., Kingsfordweg 151, 1043 GR Amsterdam, Netherlands
Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy
ATC code: A05AX04
Maralixibat is a minimally absorbed, reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).
Maralixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase the clearance of bile acids through the colon, reducing the concentration of bile acids in the serum.
The efficacy of maralixibat in ALGS patients was assessed in a 48-week trial which included an 18-week open-label active substance run-in period, a 4-week double-blind randomised withdrawal period and a long-term, open-label extension period.
Thirty-one ALGS paediatric patients with cholestasis and pruritus were enrolled, with 90.3% of patients receiving at least one medication to treat pruritus at trial entry (74.2% and 80.6% of patients receiving rifampicin and ursodeoxycholic acid, respectively). Concomitant use of these medications was allowed during the trial, but dose adjustments were prohibited during the first 22 weeks. All patients had ALGS due to JAGGED1 mutation.
Exclusion criteria included surgical interruption of the enterohepatic circulation, history or presence of any condition known to interfere with the absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine, and chronic diarrhoea requiring intravenous fluid or nutritional intervention.
After an initial 5-week dose-escalation period, patients were administered open-label treatment with maralixibat 380 mcg/kg once daily for 13 weeks; two patients discontinued treatment during this first 18 weeks of open-label run-in treatment. The 29 patients who completed the open-label run-in phase were then randomised to either continue treatment with maralixibat or receive matching placebo (n=16 placebo, n=13 maralixibat) during the 4-week double-blind randomised withdrawal period at weeks 19-22. All 29 patients completed the blinded randomised withdrawal period; subsequently, all patients received open-label maralixibat at 380 mcg/kg once daily dose for up to 48 weeks. Patients who were switched from placebo went through a dose escalation schedule similar to the initial escalation.
Randomised patients had a median age of 5 years (range: 1 to 15 years) and 66% were male. The baseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid (sBA) levels 280 (213) µmol/L, aspartate aminotransferase (AST) 158 (68) U/L, alanine transaminase (ALT) 179 (112) U/L, gamma glutamyl transferase (GGT) 498 (399) U/L, and total bilirubin (TB) 5.6 (5.4) mg/dL.
A statistically significant mean (SD) reduction in sBA versus baseline of 88 (120) and 96 (166.6) μmol/L was observed at week 18 and week 48 when patients were administered maralixibat. At the end of the placebo-controlled period, a statistically significant least squares mean (SE) difference was demonstrated between maralixibat and placebo in change in sBA from week 18 to week 22 (-114 [48.0] µmol/L; p=0.025). When the placebo group resumed treatment with maralixibat at the end of the withdrawal period, sBA reduced to levels previously observed with maralixibat treatment (see Figure 1).
Figure 1. Mean (± SE) change from baseline sBA, through week 48, all patients:
Pruritus severity was evaluated in the overall population (n=31), measured by Itch Reported Outcome Observer (ItchRO[Obs]) score. The ItchRO score is a validated 0-4 scale completed by caregivers (0=none to 4=very severe), where changes ≥1.0 have been shown to be clinically meaningful. Changes in pruritus severity between participants treated with maralixibat and those treated with placebo during the randomised withdrawal period and changes from baseline to week 18 and to week 48 were measured. The mean ItchRO(Obs) score at baseline was 2.9.
Patients administered maralixibat demonstrated a clinically meaningful change and statistically significant reductions of ItchRO(Obs) of -1.7 and -1.6 points from baseline at week 18 and week 48, respectively.
During the placebo-controlled randomised withdrawal period, patients administered maralixibat maintained pruritus reduction, whereas those in the placebo group returned to baseline pruritus scores. The difference between maralixibat and placebo in least squares mean (SE) change in pruritus from week 18 to week 22 (-1.5 [0.3]; 95% CI: -2.1 to -0.8; p<0.0001; see Figure 2) was statistically significant. After resuming maralixibat, patients from the placebo group regained improvement in pruritus by week 28. Patients administered maralixibat demonstrated sustained pruritus reduction up to 48 weeks.
Figure 2. ItchRO(Obs) weekly average morning severity score change from baseline by randomised treatment group over time, through week 48, all patients:
Improvements of variable degree in cholesterol and xanthoma severity were observed during treatment with maralixibat.
The mechanism of action of maralixibat to prevent reuptake of bile acids is expected to be similar across all age groups. Evidence of efficacy in patients younger than 12 months of age with ALGS is limited. In an open-label, single-arm study in 8 patients of 2 to 10 months of age with ALGS change in pruritus as assessed with Clinician Scratch Scale (where 0=none and 4=cutaneous mutilation, haemorrhage and scarring evident) at week 13 was mean (SD; median; range) -0.2 (1.91; -1.0; -3.0 to 3.0) and in sBA mean (SD; median; range) -88.91 µmol/L (113.348; -53.65; -306.1 to 14.4). Two patients experienced improvement in both pruritus and sBA.
The European Medicines Agency has deferred the obligation to submit the results of studies with Livmarli in one or more subsets of the paediatric population in patients with ALGS (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The target of maralixibat is in the lumen of the small intestine, such that plasma levels of maralixibat are not required and not relevant to its efficacy. Maralixibat is minimally absorbed, and plasma concentrations are often below the limit of detection (0.25 ng/mL) after single or multiple doses at therapeutic dose levels. The absolute bioavailability is estimated to be <1%.
Maralixibat absorption is relatively higher when administered in the fasted state, but no dose adjustment for food effects is necessary. Maralixibat can be taken before (up to 30 minutes) or with a meal, in the morning (see section 4.2).
Maralixibat shows high binding (91%) to human plasma in vitro. In a clinical ADME trial dosing [14C] maralixibat, circulating radioactivity was below the limit of detection at all time points. There is no apparent accumulation of maralixibat.
No metabolites have been detected in plasma, and maralixibat also undergoes minimal metabolism in the gastrointestinal tract.
Maralixibat is primarily eliminated in the faeces as unmetabolised parent compound, with 0.066% of the administered dose excreted in the urine.
No clinically significant differences in the pharmacokinetics of maralixibat were observed based on age, sex, or race.
Clinical studies of maralixibat included ALGS patients with some level of liver impairment. The majority of ALGS patients presented with some degree of hepatic impairment according to the NCI-ODWG classification due to the disease. Whether this classification is, however, appropriate in cholestatic disease, and in ALGS to predict the influence on PK of the compound is currently unclear. Maralixibat is minimally absorbed, and animal data indicate that the very low plasma levels are due to low absorption and not a first pass effect in the liver, and plasma levels of maralixibat were not increased in ALGS patients with liver impairment according to the NCI-ODWG. However, the PK of maralixibat have not been systematically investigated in patients classified according to the Child-Pugh classification (patients with cirrhosis and signs of decompensation).
The pharmacokinetics of maralixibat were not studied in patients with impaired renal function, including those with ESRD or those on haemodialysis. However, renal impairment is not expected to impact maralixibat PK due to the low systemic exposure and lack of urinary excretion.
Non-clinical data reveal no specific hazard for humans based on studies of safety pharmacology, secondary pharmacology, repeated-dose toxicity, genotoxicity, fertility, toxicity to reproduction and development, and juvenile animal toxicity.
There were higher incidences of bronchiolo-alveolar adenoma and carcinoma following oral administration of maralixibat to male TgRasH2 mice at doses of 25 mg/kg/day for 26 weeks, but the incidence of these lung findings remained within the documented range of historical control data for the mouse strain, and human relevance of these findings is unknown. A 2-year rat carcinogenicity study is still ongoing.
No effects on fertility were observed in female rats treated orally with up to 2 000 mg/kg/day or in male rats treated orally with up to 750 mg/kg/day.
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