Odevixibat (1) – Bylvay®

• Clinical trials
  • The PEDFIC1 trial is a multicentre, double-blind, randomised, placebo-controlled Phase III trial investigating the efficacy and safety of odevixibat in children and adolescents aged ≥ 6 months to ≤ 18 years with a genetically confirmed diagnosis of the PFIC1 and PFIC2 subtypes.
  • The PEDFIC2 study is an open-label, single-arm, multicentre Phase IIIextension study with a treatment duration of 72 weeks designed to investigate the long-term efficacy and safety of odevixibat exclusively at a dose of 120 μg/kg/day in patients with PFIC.

Children, adolescents and adults aged 6 months and over with progressive familial intrahepatic cholestasis

• For children, adolescents and adults aged 6 months and over with progressive familial intrahepatic cholestasis, there is a hint of a minor additional benefit.
• Taking the available results as a whole, there is a hint of a minor additional benefit of odevixibat based on the advantage observed for the endpoint of pruritus.
• The strength of the evidence is classified as ‘hint’ due to uncertainties arising from the choice of a fixed dose of odevixibat in both study arms and with regard to the assessment tool used to measure the pruritus endpoint (AlbireoObsRO).
• mortality
  • Deaths were recorded in the PEDFIC1 study as part of the safety assessment. No deaths occurred.
• Morbidity – Pruritus
  • The patient-reported assessment of pruritus as a distressing symptom in the clinical picture of PFIC is considered to be relevant to patients.
  • The ObsRO data are subject to uncertainty, as the results of the PEDFIC1 study were used simultaneously for the development and validation of the instrument.
  • In the analyses of the improvement in pruritus using the eDiary (Albireo ObsRO), a statistically significant advantage of odevixibat was observed for the operationalisation ‘proportion of positive pruritus ratings’ at both dosages, and for the operationalisation ‘proportion of participants with ≥ 50% positive pruritus ratings’, a statistically significant advantage of odevixibat was observed at the 40 µg/kg/day dose.
  • For the pruritus endpoint, a statistically significant advantage of odevixibat was observed both in the operationalisation “proportion of positive pruritus assessments” for both doses and in the operationalisation ‘Participants with ≥ 50% positive pruritus assessment’, a statistically significant advantage of odevixibat at a dose of 40 µg/kg/day.
• Morbidity – Sleep quality
  • The clinical relevance of the symptoms of fatigue and sleep patterns in the study participants – which were also recorded via the eDiary – is unclear, and the effects of sleep deprivation and fatigue on participants’ daily activities or behaviour are not adequately captured by the eDiary items.
  • For this reason, the symptoms of fatigue and sleep patterns recorded via the eDiary are not taken into account.
• Morbidity – Surgical procedures
  • In the PEDFIC1 study, no patient-relevant surgical procedures, such as surgical bile diversions or liver transplants, were performed.
• Morbidity – Growth deficit
  • Anthropometric parameters can be assessed as patient-relevant morbidity parameters, particularly in children with characteristic, disease-related growth disorders.
  • In the PEDFIC1 study, the z-scores for height, weight and body mass index (BMI) at weeks 12 and 24 were recorded in comparison with baseline, using standardised growth charts.
  • However, no statistically significant advantage or disadvantage was observed in the anthropometric parameters during treatment with odevixibat at week 12 or week 24.
  • There is no statistically significant advantage or disadvantage with regard to the endpoint of growth deficits.
• Health-related quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • With regard to the overall population, the study did not achieve the required response rate of at least 70% for either the self-reports or the parent-reported assessments. Consequently, no usable data on health-related quality of life are available from the PEDFIC1 study.
• Side effects
  • A post hoc analysis of the differences between the treatment groups was carried out within the PEDFIC1 study. For adverse events (AEs), only one-sided p-values were reported, without this approach being plausibly justified by a specific hypothesis.
  • Due to the lack of suitable p-values, only the relative risk and confidence intervals are reported. The confidence intervals are used for evaluation.
  • In the PEDFIC1 study, at least one AE occurred in just over 80 per cent of participants in each treatment group.
  • According to the definition in the study protocol, severe AEs were those that rendered the subject incapacitated or unable to carry out normal activities. These occurred in 2 subjects each from the odevixibat 120 μg/kg/day treatment group and the placebo group, and in 1 subject from the odevixibat 40 μg/kg/day treatment group.
  • Serious AEs occurred in 3 out of 19 (16 per cent) participants in the odevixibat 120 μg/kg/day treatment arm and in 5 out of 20 (25 per cent) participants in the placebo arm.
  • In the odevixibat arm (120 μg/kg/day), an AE with the preferred term ‘diarrhoea’ led to discontinuation of the study medication in one person.
  • The analyses presented on the overall rates of AEs show, based on the confidence intervals, neither advantages nor disadvantages of odevixibat with regard to side effects.
  • Overall, uncertainties remain regarding the assessment of side effects.
• Overall assessment
  • No deaths occurred in the PEDFIC1 study.
  • In the morbidity endpoint category, the endpoints ‘pruritus’, ‘sleep quality’, ‘surgical procedures’ and ‘growth deficits’ were recorded.
  • For the pruritus endpoint, a statistically significant advantage of odevixibat was observed both in the operationalisation ‘proportion of positive pruritus assessments’ for both doses and in the operationalisation ‘subjects with ≥ 50% positive pruritus assessment’, a statistically significant advantage of odevixibat was observed at the 40 µg/kg/day dose.
  • No surgical procedures occurred during the study. No statistically significant advantage or disadvantage was observed for the endpoint ‘growth deficits’.
  • No usable data on health-related quality of life are available from the study.
  • With regard to side effects, the confidence intervals for the overall rates of AEs indicate neither advantages nor disadvantages. Overall, uncertainties remain, even when taking the EMA’s conditions into account.
  • Taking an overall view of the available results, a minor additional benefit of odevixibat is identified based on the advantage observed for the endpoint of pruritus.

Courtesy translation only, please refer to the German original.