Pegzilarginase (1) – Loargys®

• Clinical trials
  • To conduct the benefit assessment, the pharmaceutical manufacturer has included the Phase III PEACE trial (CAEB1102-300A) in the dossier. This was a randomised, double-blind, multicentre trial in which the efficacy and safety of pegzilarginase (n = 21) were compared with those of placebo (n = 11), each in combination with individualised disease management, in patients aged 2 years and over with arginase-1 deficiency over a period of 24 weeks.

Adults, adolescents and children aged 2 years and over with arginase-1 deficiency (hyperargininemia)

• mortality
  • Mortality was recorded as part of the safety monitoring. No deaths occurred during the course of the study.
• morbidity
  • When interpreting the results on morbidity presented in the resolution, it should generally be noted that the patients differed in key baseline characteristics relating to disease burden, age, individual disease management and also in the baseline values of the endpoints assessed, in each case in favour of the intervention arm.
  • Arginine concentration is a clinically relevant laboratory parameter in this therapeutic indication, used for diagnosis and to guide treatment.
  • In the PEACE study, a significant reduction in arginine concentration was observed after 24 weeks of treatment with pegzilarginase compared with baseline, whilst no change was observed with placebo. There is a statistically significant difference between the treatment arms in favour of pegzilarginase.
  • However, no valid data could be identified to show what effects a specific change in arginine concentration has on the symptoms specific to each individual patient. Therefore, this endpoint is considered only as a supplementary measure.
  • In the PEACE study, walking ability was assessed as an indicator of patients’ physical performance (endurance) using the 2MWT (the distance patients can walk within 2 minutes). The use of a walking aid was permitted during the test. No statistically significant difference was observed in the changes in absolute walking distance from baseline to week 24 between the study arms.
  • For the present benefit assessment, the continuous analysis of the mean changes in the GFAQ between baseline and week 24 is used. No statistically significant difference was observed between treatment with pegzilarginase and placebo.
  • In the PEACE study, there was no statistically significant difference between placebo and pegzilarginase in the change in gross motor ability, as measured by dimension E of the GMFM, from baseline to week 24.
  • Functional mobility was to be assessed in the PEACE study using the FMS. A restriction in mobility caused by hyperargininemia and an associated dependence on mobility aids is generally considered to be relevant to patients. However, the FMS does not measure disease-specific dependence on mobility aids or assistance, but rather general dependence – without taking into account other direct morbidity and quality-of-life parameters. Consequently, it cannot be ruled out that, for some patients, factors such as the developmental process of learning to walk may lead to an improvement independent of the study medication, or that circumstances unrelated to the disease – such as a fall or the availability of walking aids – may influence the result. The endpoint is therefore not used for the benefit assessment.
  • The VABS-II endpoint, which was assessed in the PEACE study and measures the ability to cope with the challenges of daily life, is not taken into account in the benefit assessment due to ambiguities in its operationalisation.
  • The CaGI-S is a questionnaire which, in this context, is used as part of an external assessment by carers to gauge the current deficits of study participants in terms of mobility, everyday skills, social skills and adaptive behaviour, compared with other people of the same age group without an ARG1 deficiency. This endpoint is not used due to unclear validity.
  • Although the CaGI-C, which is designed to capture the carer’s impression of changes in the quality of mobility aspects, everyday skills, social skills and adaptive behaviour, appears to be more valid than the CaGI-S, no analyses with adequate effect estimates are available. The endpoint cannot therefore be taken into account for the present benefit assessment.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The PedsQL is an established, generic instrument for measuring health-related quality of life, comprising four dimensions (physical, emotional, social and school-related functioning).
  • In the PEACE study, the PedsQL was administered to patients aged between 2 and 18 years. The assessment was carried out via self-report or – where the patient was unable to self-report or was under 5 years of age – via parent-reported assessment. As a joint evaluation of the PedsQL’s self-assessment and parent-reported assessment was deemed inappropriate, the pharmaceutical manufacturer submitted separate evaluations of the self-assessment and parent-reported assessment as part of the commenting procedure. However, the analyses submitted subsequently are not used for the present benefit assessment. For the parent-reported PedsQL, the response rate was too minor and, furthermore, a ‘missing completely at random’ assumption cannot be made.
  • The self-assessment is not taken into account for the benefit assessment due to validity limitations. For some individuals, raters’ assessments were available in addition to the self-assessments. There were neither formalised criteria nor documented reasons for the psychological assessment of the ability to self-assess. The classification was made on a case-by-case basis, drawing on the professional expertise of the trial staff or the psychologist. It is therefore unclear whether these individuals were capable of providing a valid self-assessment, and this could not be conclusively clarified during the commenting procedure either.

Courtesy translation only, please refer to the German original.