Sepiapterin (1) – Sephience®

• Clinical trials
  • The PTC923-MD-004-PKU study (004 for short) is a single-arm long-term extension (LTE) study investigating the efficacy and safety of sepiapterin.

Adults and paediatric patients with phenylketonuria-associated hyperphenylalaninaemia

• For adults and paediatric patients with phenylketonuria-associated hyperphenylalaninaemia (HPA), there is a hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• The G-BA therefore classifies the extent of the additional benefit of sepiapterin for the treatment of adults and paediatric patients with phenylketonuria-associated hyperphenylalaninaemia as non-quantifiable, as the scientific evidence does not permit quantification.
• The strength of the evidence is assessed as a ‘hint’.
• mortality
  • Deaths were documented as part of the safety monitoring. No deaths occurred during the RCT phase of the APHENITY and AMPLIPHY studies.
• Morbidity – Blood phenylalanine (Phe) concentration
  • In the therapeutic indication, the Phe concentration in the blood is a clinically relevant parameter used for diagnosis and to guide treatment.
  • The ‘European guidelines on the diagnosis and treatment of phenylketonuria’ recommend a therapeutic target range for phenylalanine (Phe) in the blood of between 120 µmol/l and 360 µmol/l for children up to 12 years of age. For individuals aged over 12 years with PKU, the target range is between 120 and 600 µmol/l.
  • Even taking into account the variability in clinical presentation between individual patients and the limited evidence regarding the threshold value in adults, reducing the Phe concentration in the blood to below the thresholds in this therapeutic indication represents a clinical goal in the treatment of patients with phenylketonuria.
  • However, the significance of a specific change in blood Phe concentration in relation to patient-specific symptoms remains unclear. The endpoint is therefore not used to quantify the additional benefit, but is presented as supplementary information in the resolution.
  • In the continuous analyses of changes in Phe levels at week 5/6 (APHENITY, study phase 2) and at week 3/4 (AMPLIPHY; study phase 2), both studies showed a marked reduction in Phe levels in the sepiapterin arm compared with baseline. A statistically significant difference was observed both in comparison with placebo (APHENITY) and in comparison with sapropterin (AMPLIPHY).
• Morbidity – Estimated daily phenylalanine intake
  • Long-term adherence to a strict phenylalanine-restricted diet combined with the intake of synthetic amino acid mixtures (to prevent malnutrition) currently forms the cornerstone of phenylketonuria therapy. Reducing phenylalanine levels below the threshold values whilst maintaining a normalised natural protein intake can therefore be regarded as a therapeutic goal in this therapeutic indication.
  • However, as the study protocol stipulated that participants’ protein intake should be kept as stable as possible throughout the study duration, this endpoint does not allow any conclusion to be drawn as to whether sepiapterin enables a normal or improved natural protein intake whilst simultaneously reducing blood Phe concentrations.
  • The data for the endpoint ‘Estimated daily phenylalanine intake’ are therefore not presented due to a lack of statistical significance.
• Health-related quality of life
  • In the AMPLIPHY study, health-related quality of life was assessed using the Phenylketonuria Quality of Life (PKU-QoL) questionnaire. However, the pharmaceutical manufacturer has not submitted any data on this endpoint, as the study results are not suitable for assessing additional benefit due to the low response rate.
• Side effects
  • In both studies, neither serious adverse events (AEs) nor AEs leading to discontinuation of the study medication occurred in Part 2 of the study. No severe AEs occurred in the APHENITY study, and in the AMPLIPHY study they occurred in fewer than 5% of patients.
• Overall assessment
  • This assessment is based on the results of the APHENITY study (Study 003) and the AMPLIPHY study (Study 301). Both studies consist of two phases each. In Phase 1, all participants were assessed for a response to the active ingredient sepiapterin. In Phase 2, only those participants who had shown a response to the active ingredient sepiapterin were included.
  • When evaluating the available study data, it is considered critical that only those patients who had already shown a response to treatment with the active ingredient sepiapterin were included. This restriction of the study population to sepiapterin responders has a major impact on the certainty of the results. Furthermore, limitations arise from the short observation periods of the comparative study phases, which lasted 6 weeks, of which Sepiapterin was administered at the authorised dose for only 2 weeks (APHENITY) or 4 weeks (AMPLIPHY).
  • For the endpoint of blood phenylalanine concentration, a statistically significant difference in favour of sepiapterin was observed both in comparison with placebo (APHENITY) and in comparison with sapropterin (AMPLIPHY). This laboratory parameter is clinically relevant for the diagnosis and monitoring of the disease; however, the significance beyond this of a specific change in blood phenylalanine concentration on the symptoms specific to each individual patient remains unclear.
  • Overall, due to the limitations mentioned, the available data cannot be evaluated and are therefore not suitable for quantifying the extent of the additional benefit.

Courtesy translation only, please refer to the German original.