Pegvaliase (1) – Palynziq®

• Clinical trials
  • Study 165-301 is an uncontrolled study in which different dosages of the active ingredient pegvaliase were compared during an induction, a titration and a maintenance phase.
  • Study 165-302 is a Phase III study comprising four distinct study phases.

Patients aged 16 years and over with phenylketonuria (PKU) whose blood phenylalanine levels are not adequately controlled despite prior use of available treatment options (blood phenylalanine levels above 600 μmol/l)

• For patients aged 16 years and over with phenylketonuria whose blood phenylalanine levels are not adequately controlled despite prior use of available treatment options (blood phenylalanine levels above 600 μmol/l), there is a hint of a non-quantifiable additional benefit for pegvaliase, as the scientific data do not permit quantification.
• Overall, for Pegvaliase in the treatment of patients aged 16 years and over with phenylketonuria whose blood phenylalanine levels are not adequately controlled despite prior use of available treatment options (blood phenylalanine levels above 600 μmol/l), there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• mortality
  • Fatalities were recorded as part of the monitoring of adverse events.
  • In study 165-301, one death occurred which was not related to the administration of the study medication. The study participant died as a result of an electric shock.
  • No deaths were recorded during the course of study 165-302.
  • No conclusions regarding the extent of the additional benefit can be drawn from the mortality data.
• Morbidity – Phenylalanine concentration (Phe concentration) in the blood
  • In the therapeutic indication, the Phe concentration in the blood is a clinically relevant parameter used for diagnosis and to guide treatment.
  • In study 165-301, the Phe concentration in the blood decreased by an average of 403.7 μmol/l from baseline by week 20, to a mean of 807.5 μmol/l. From week 24 onwards, the proportion of patients for whom phenylalanine concentration data are available is less than 70 per cent of the study population. For this reason, the results are not presented.
  • In study 165-302, the mean blood Phe concentration during the 8-week withdrawal trial in study phase 2, the mean Phe concentration in the blood rose to a statistically minorly lower level when the respective dose of pegvaliase was administered compared with when the respective placebo was administered, both for the low dose of 20 mg/day and for the higher dose of 40 mg/day.
  • The data on the mean Phe concentration in the blood from Phase 4 (uncontrolled long-term extension) of Study 165-302 are not presented, as the calculated response rate at all measurement time points during Phase 4 of Study 165-302 was < 70 per cent.
  • No conclusions regarding the extent of the additional benefit can be drawn from the morbidity data.
• quality of life
  • No data on health-related quality of life are available.
• Side effects
  • In studies 165-301 and 165-302, almost all patients experienced an adverse event (AE).
  • In study 165-301, 29 patients (11.1 %) experienced an AE that led to discontinuation of the study medication. The most common of these AEs, based on Preferred Term, were ‘anaphylactic reactions’ (n = 6; 2.3%) and ‘arthralgia’ (n = 6; 2.3%).
  • In addition, 39 patients (14.9 %) experienced at least one AE of grade 3 or higher. Immune system disorders of grade 3 or higher occurred in 16 patients (6.1 %) in study 165-301.
  • In study 165-301, 26 patients (10.0 %) experienced at least one SAE. SAEs relating to immune system disorders occurred in 14 patients (5.4 %).
  • In study 165-302, 12 participants (5.6 %) experienced an AE that led to discontinuation of the study medication.
  • In addition, 30 patients (14.0 %) experienced at least one AE of grade 3 or higher.
  • In study 165-302, 26 patients (12.1 %) experienced at least one SAE. Psychiatric SAEs occurred in 2 patients (6.3%) who were treated with 40 mg/day of pegvaliase during phase 2 of study 165-302.
  • Anaphylaxis according to NIAID/FAAN criteria (defined as an AEs of special interest) occurred in 18 patients (6.9 %) in Study 165-301 and in 11 patients (5.1 %) .
  • As the majority of patients from Study 165-301 subsequently participated in Study 165-302, patients who experienced an AE in Study 165-302 may also have experienced an AE in Study 165-301. The number of patients to whom this applies is unclear.
  • No effect estimators or p-values were presented for the comparisons during Study Phase 2 (20 mg/day pegvaliase vs. ‘low-dose placebo’; 40 mg/day pegvaliase vs. ‘high-dose placebo’) of Study 165-302, no effect estimates or p-values were presented.
  • No conclusions regarding the extent of the additional benefit can be drawn from the data on side effects.
• Overall assessment
  • For the treatment of patients aged 16 years and over with phenylketonuria (PKU) whose blood phenylalanine levels are not adequately controlled despite prior use of available treatment options (blood phenylalanine levels above 600 μmol/l), results on mortality, morbidity and side effects are available from the pivotal registration trials 165-301 and 165-302.
  • No conclusions regarding the extent of the additional benefit can be drawn from the mortality data.
  • In the morbidity category, a statistically significant change in blood Phe concentration in favour of treatment with pegvaliase compared with placebo was demonstrated after 8 weeks, as well as a reduction in blood Phe concentration compared with baseline over a period of 20 weeks. 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 Phe concentration for the symptoms specific to each individual patient remains unclear. For the endpoint category of morbidity, no conclusions regarding the extent of the additional benefit can be drawn on the basis of the data presented. No data are available for the benefit assessment with regard to quality of life.
  • No conclusions regarding the extent of the additional benefit can be drawn from the data on side effects. In summary, the available results are, on balance, classified as non-quantifiable in terms of their extent, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.