Maralixibat (2) – Livmarli®

• Clinical trials
  • The MARCH-PFIC trial is a multinational, randomised, double-blind Phase III trial in which maralixibat was compared with placebo in patients with PFIC aged 12 months to < 18 years.
  • The RISE trial is an open-label, multicentre, uncontrolled Phase II clinical study investigating maralixibat in infants under 12 months of age with cholestatic liver diseases (PFIC or Alagille syndrome).

Adults, adolescents and children aged 3 months and over with progressive familial intrahepatic cholestasis

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification
• mortality
  • No deaths occurred during the study.
• Morbidity – pruritus assessed via patient diary (ItchRO)
  • The response rate for the ItchRO(Obs) was too minor, meaning that only the results of the ItchRO(Obs) can be taken into account in the benefit assessment.
  • Based on this operationalisation, a statistically significant advantage in favour of maralixibat over placebo is evident for the pruritus endpoint.
• Morbidity – Physical development
  • In the overall population of the MARCH-PFIC study, the analyses for weeks 18–26 compared with baseline show a statistically significant advantage of maralixibat over placebo for both height and body weight.
  • The change in body weight is more pronounced in the MARCH-PFIC study and is assessed by the G-BA as a clinically relevant improvement.
  • The effect on height is less pronounced than that on body weight, meaning that the period for a comparative assessment from weeks 18 to 26 compared with baseline is too short to conclusively assess the clinical relevance of the changes in height.
• Morbidity – reduction in serum bile acid concentration
  • For the change in sBA levels between baseline and the average of weeks 18–26, there is a statistically significant advantage of treatment with maralixibat compared with placebo.
  • The endpoint ‘reduction in serum bile acid concentration’ is therefore not taken into account in the benefit assessment.
• Morbidity – Fatigue
  • For the endpoint of fatigue, the change in the PedsQL Fatigue score (parent-reported) from baseline to weeks 18–26 shows a statistically significant advantage of maralixibat compared with placebo.
  • Furthermore, the confidence interval for Hedges’ g lies entirely above the threshold value of 0.2.
• Health-related quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • Based on the parent-reported version of the PedsQL, no statistically significant differences were observed between the treatment arms.
• Side effects
  • The safety results for the overall population of the MARCH-PFIC study show no statistically significant differences between the treatment groups, neither in terms of SAEs and severe AEs nor in terms of therapy discontinuations due to AEs.
  • In detail, for the event of diarrhoea (an AEs of particular interest), there was a statistically significant disadvantage of maralixibat compared with placebo.
• Overall assessment
  • In the morbidity category, a statistically significant advantage in favour of maralixibat over placebo was observed for the endpoint pruritus, assessed using ItchRO(Obs), and for the endpoint fatigue, assessed using PedsQL-Fatigue.
  • Furthermore, for the physical development endpoint, a statistically significant advantage of maralixibat over placebo was observed for both height (z-score) and body weight (z-score).
  • The difference in body weight is considered clinically relevant.
  • For the category of health-related quality of life, assessed using the PedsQL, and for the category of side effects, no statistically significant differences were observed between the treatment arms.
  • The positive effects observed for the endpoints of pruritus, fatigue and physical development (body weight) are therefore not offset by any negative effects.
  • Due to the excessively high dosage of maralixibat in children under 5 years of age in the MARCH-PFIC study, the transferability of the study results to the German healthcare context is questionable.
  • The extent of the advantages demonstrated in the morbidity endpoint category cannot therefore be quantified overall.
  • Furthermore, no comparative data are available for the patient population of infants aged 3 to < 12 months, which is also covered by the marketing authorisation.
  • In its overall assessment of the available results regarding patient-relevant endpoints, the G-BA therefore classifies the extent of the additional benefit of maralixibat for the treatment of progressive familial intrahepatic cholestasis in adults, adolescents and children aged 3 months and over, as non-quantifiable, based on the criteria set out in Section 5(8) in conjunction with Section 5(7), first sentence, points 1 to 4 of the AM-NutzenV, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.