Maralixibat (1) – Livmarli®

• Clinical trials
  • The ICONIC trial is an open-label, long-term study with a double-blind, placebo-controlled, randomised withdrawal phase (RW phase) designed to investigate the safety and efficacy of maralixibat in children aged 12 months up to and including 18 years with ALGS.
  • The MRX-801 study is an open-label, uncontrolled Phase II study designed to investigate the safety and tolerability of maralixibat in the treatment of infants (< 12 months) with cholestatic liver diseases (PFIC or ALGS).
  • The GALA-MRX-ALGS study is an investigation into long-term treatment with maralixibat in patients with ALGS, compared with an external control cohort from the GALA study.

Children, adolescents and adults aged 2 months and over with cholestatic pruritus associated with Alagille syndrome

• For children, adolescents and adults aged 2 months and over with cholestatic pruritus associated with Alagille syndrome, there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, based on the study design, there is a hint of a non-quantifiable additional benefit for maralixibat, as the scientific evidence does not permit quantification.
• mortality
  • Deaths were recorded in the ICONIC and MRX-801 studies as part of the safety monitoring. No deaths occurred in either study.
• Morbidity – Pruritus assessed via patient diary (ItchRO)
  • The endpoint of pruritus was assessed in the ICONIC and MRX-801 studies using the electronic patient diary Itch Reported Outcome (ItchRO), which was completed in the morning and evening to record the severity of itching during the night until waking and during the day, respectively, using a 5-point Likert scale.
  • Whilst the mean values of the weekly averages for the morning assessment (nocturnal pruritus) at baseline were still balanced between the maralixibat and placebo groups, the assessment at week 18, the time of randomisation and the start of the RW phase, a slightly lower value was observed in the placebo arm. By week 22, the value in the placebo arm had then risen again to almost the baseline level, whilst it remained at the lower level in the maralixibat group. This difference is statistically significant.
  • Analyses are available both for the proportion of participants who achieved a weekly average score of ≤ 1 point (morning assessment, as reported by patients and carers) at week 22, and for the proportion of days with a score of ≤ 1 point (measured in the morning, as reported by patients and carers). In the latter case, a statistically significant difference was observed in favour of maralixibat.
  • In the continuous analyses of the uncontrolled data over the entire course of the study, no recurrence of pruritus was observed up to week 48.
  • However, uncertainties remain regarding the validation of the assessment tool, and no information is provided on missing values.
  • With regard to the natural course of the disease, it should be noted that the affected patients suffer from extremely severe pruritus, which is generally difficult to treat effectively.
  • Taken together, the present data show a significant reduction in pruritus during the RW phase following administration of maralixibat compared with placebo; however, the extent of this reduction is non-quantifiable.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The PedsQL 4.0 measures general health-related quality of life in children and adolescents. It consists of four multidimensional scales (Physical Function, Emotional Function, Social Functioning and School Function) with a total of 23 items and three summary scores: total score, physical health summary score and psychosocial health summary score.
  • The PedsQL was analysed using mean differences compared with baseline and week 18 for the RW phase. No statistically significant differences were observed between the treatment arms; neither in the parent nor in the child version.
• Side effects
  • The pharmaceutical manufacturer provides analyses of all AEs across the various study phases. According to SAP, only newly occurring or worsening AEs were recorded in each study phase. It follows that the AE results for the RW phase are not meaningful, as they do not include AEs that had already occurred during the preceding 18 weeks of treatment.
  • It remains unclear whether, on the basis of the provisions in the protocol, a sufficient distinction could be made between symptoms of the underlying condition and side effects. However, taking into account the available safety data from the RW phase, it can be assumed that symptoms were also classified as AEs.
  • Given the limitations of the study design presented, the minor sample size and the constraints in the collection and analysis of safety data regarding the recording of disease symptoms, it is not possible to make a definitive assessment of the safety of maralixibat in children and adolescents with ALGS.
• Overall assessment
  • For the benefit assessment of maralixibat for the treatment of cholestatic pruritus in adults, adolescents and children aged 2 months and older with Alagille syndrome (ALGS), results are available from the uncontrolled ICONIC study on mortality, morbidity, health-related quality of life and side effects.
  • Within the morbidity endpoint category, the pruritus endpoint from the ICONIC study is used for the present benefit assessment. For the pruritus endpoint, the RW phase shows a statistically significant advantage of maralixibat over placebo in the operationalisation ‘proportion of days with a score ≤ 1 point’ in both the carer-reported and patient-reported ItchRO.
  • Health-related quality of life was assessed in the ICONIC study using a measurement tool suitable for the paediatric patient population. No statistically significant differences were observed during the RW phase. Due to the study design, no definitive assessment can be made.
  • With regard to the results on side effects, treatment with maralixibat was associated with some severe (CTCAE Grade 3 or 4) and serious adverse events, as well as therapy discontinuations due to adverse events. A definitive assessment of the safety of maralixibat in children and adolescents with ALGS is not possible given the study design presented.
  • Overall, the administration of Maralixibat results in a significant reduction in pruritus, although the extent of this reduction is non-quantifiable.

Courtesy translation only, please refer to the German original.