Glycerolphenylbutyrat (1) – Ravicti®

• Clinical trials
  • The pivotal study HPN-100-006 was conducted as a two-arm, parallel-group trial to determine the efficacy and safety of glycerol phenylbutyrate compared with sodium phenylbutyrate in patients aged ≥ 18 years with urea cycle disorders.
  • Furthermore, the single-arm studies HPN-100-005 (6–17 years, N=11), for the benefit assessment of the marketing authorisation, HPN-100-005SE (6–17 years, N=17), HPN-100-012 (29 days–6 years, N=15) and HPN-100-012SE (29 days–6 years, N=23), HPN-100-007 (6–17 years; ≥ 18 years, N=60), HPN-100-009 (2 months–2 years, N=10), HPN-100-011 (29 days–17 years; ≥ 18 years, N=88), which largely included patients aged between 29 days and 18 years.

adult and paediatric patients aged ≥ 2 months with urea cycle disorders that cannot be managed by dietary protein restriction and/or amino acid substitution alone

• For adult and paediatric patients aged ≥ 2 months with urea cycle disorders that cannot be managed by dietary protein restriction and/or amino acid supplementation alone, glycerol phenylbutyrate has been shown to provide an unquantifiable added benefit as an adjunct to dietary protein restriction and, in some cases, to dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free calorie supplements) in some cases.
• Due to the methodological limitations of the studies 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.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence currently does not permit a quantifiable assessment of the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • In the HPN-100-006 study, no deaths occurred under either sodium phenylbutyrate or glycerol phenylbutyrate treatment.
• Morbidity – 24-hour AUC of ammonia concentration in the blood
  • The results for the 24-hour AUC of blood ammonia concentration from the two studies mentioned above short-term studies show that the blood ammonia concentration remains within the normal range during treatment with glycerol phenylbutyrate, thereby stabilising the pathologically altered ammonia level underlying the enzyme deficiency.
  • For neither study are there any usable data on morbidity apart from the laboratory parameters (including blood ammonia concentration).
• quality of life
  • In the study, quality of life was assessed exclusively at baseline, meaning that no comparative conclusions can be drawn from the data.
• Overall assessment
  • To assess the extent of the additional benefit of glycerol phenylbutyrate, the overall review includes results on mortality, morbidity and side effects from a randomised, actively controlled, double-blind, 4-week crossover trial with a low risk of bias.
  • The results of this pivotal RCT show no statistically significant difference between treatment with glycerol phenylbutyrate and sodium phenylbutyrate for any of the endpoints.
  • There is no difference either for the endpoint of 24-hour AUC of blood ammonia concentration or for the endpoint of hyperammonaemic crises.
  • Due to the minor number of hyperammonaemic crises that occurred in the study, the relevance of the lack of a difference cannot be assessed.
  • The data on side effects show no differences between the treatment arms in the study.
  • However, as no reliable data are available for children and adolescents, the effects of glycerol phenylbutyrate in this age group cannot be conclusively assessed.

Courtesy translation only, please refer to the German original.