Glycerolphenylbutyrat (2) – Ravicti®

• Clinical trials
  • The HPN-100-009 study was an open-label, multicentre, Phase IV study without a control arm, which investigated the safety, efficacy and pharmacokinetics of glycerol phenylbutyrate in children aged up to two years.

Infants aged 0 to < 2 months with urea cycle disorders that cannot be treated by dietary protein restriction and/or amino acid substitution alone

• For infants aged 0 to < 2 months with urea cycle disorders that cannot be treated by dietary protein restriction and/or amino acid substitution alone, glycerol phenylbutyrate offers a non-quantifiable additional benefit.
• Due to the methodological limitations of the study and the generally limited evidence base, the G-BA classifies the extent of the additional benefit of glycerol phenylbutyrate, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing, as non-quantifiable.
• Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit into one of the categories ‘minor’, ‘considerable’ or ‘major’ is not possible on the basis of the data submitted. An additional benefit exists, but it is non-quantifiable because the scientific evidence currently does not permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • No deaths occurred.
• morbidity
  • A successful switch to glycerol phenylbutyrate with controlled ammonia was based on the study staff answering a relevant question.
  • As the majority of children included in the study (n = 10; 62.5% of the safety population) had already discontinued another medication prior to switching to glycerol phenylbutyrate, a successful switch is not considered to be directly relevant to patients.
  • Due to the lack of clear patient relevance and the limited validity, the results of this endpoint are not used to assess the extent of the additional benefit.
  • Hyperammonaemic crises are considered to be of clinical relevance. However, the uncertainties mentioned in relation to the endpoint ‘Successful switch to glycerol phenylbutyrate with controlled ammonia levels’ regarding the recording of signs and symptoms of hyperammonaemia, as well as the measurement of ammonia levels, remain.
  • During the study, a total of 5 children experienced at least one hyperammonaemic crisis. All hyperammonaemic crises occurred during the safety extension phase. The rate of hyperammonaemic crises per child per day is 0.003.
• quality of life
  • No data on health-related quality of life were collected.
• Side effects
  • All children experienced at least one adverse event (AE) during the study, with six children (37.5 per cent) experiencing at least one Grade 3 AE and eleven children (68.8 per cent) experienced at least one serious adverse event (SAE) during the study.
  • In terms of system organ class, the most common Grade 3 AEs occurred in the categories ‘infections and infestations’ and ‘metabolic and nutritional disorders’. The only Grade 3 AE to occur in more than one child was ‘hyperammonaemia’. No Grade 4 or 5 adverse events occurred.
  • In one child, elevated liver enzyme levels, which were classified as a Grade 1 AE, led to discontinuation of the study medication and also to exclusion from the study.
  • In terms of system organ class, the most common serious adverse events (SAEs) also occurred in the categories “Infections and parasitic diseases” and “Metabolic and nutritional disorders”. The most common SAE based on Preferred Terms was “hyperammonaemia”. No other SAE occurred in more than one child.
  • According to the EPAR, the safety profile of glycerol phenylbutyrate in children aged < 2 months is generally consistent with the known safety profile of glycerol phenylbutyrate in older patients.
  • However, based on the available data, it remains unclear how many children experienced which AEs before the end of their first two months of life.
• Overall assessment
  • To assess the extent of the additional benefit of glycerol phenylbutyrate for infants aged 0 to < 2 months, the overall review presents results on mortality, morbidity and side effects from the open-label Phase IV study HPN-100-009, which had no control arm and a high potential for bias.
  • During the study period, a total of 5 out of 16 children receiving glycerol phenylbutyrate experienced at least one hyperammonaemic crisis. It is not possible to assess the extent of the additional benefit with regard to mortality and morbidity due to the lack of a comparator. No data on quality of life are available. It is also not possible to assess the extent of the additional benefit with regard to side effects due to the lack of a comparator.

Courtesy translation only, please refer to the German original.