RADAMTS13 (1) – Adzynma®

• Clinical trials
  • Study 281102 is a multicentre, randomised, controlled, open-label, two-phase crossover study, followed by a single-arm extension phase, which investigated the efficacy and safety of rADAMTS13 as a prophylactic and on-demand (on-demand) treatment for patients with cTTP.
  • In study 281102, rADAMTS13 was compared with standard therapy (SoC – Standard of Care, plasma-based therapy).

a) Adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) receiving rADAMTS13 as a prophylactic treatment

• Adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) receiving rADAMTS13 as prophylactic treatment
• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification
• The strength of the evidence is therefore classified as ‘hint’.
• mortality
  • Fatalities
  • Deaths were recorded as part of study 281102 within the safety endpoints from the first dose of the study medication until the end of the study or its discontinuation.
  • No deaths occurred during the course of the study.
  • The endpoint ‘deaths’ is irreversible and therefore cannot be meaningfully investigated in a crossover study design. The present study design is thus not suitable for comparing the number of deaths between the treatment arms.
• Morbidity – acute cTTP events
  • The incidence of acute cTTP events during prophylactic treatment of cTTP constitutes the primary endpoint of study 281102.
  • Acute cTTP events were defined as the simultaneous occurrence of thrombocytopenia, measured by platelet count, and microangiopathic haemolytic anaemia (MAHA), measured by an increase in lactate dehydrogenase (LDH).
  • The results show no statistically significant difference between treatment with rADAMTS13 and treatment with standard of care (SoC) in terms of the incidence of acute cTTP events during prophylactic treatment of cTTP.
  • Platelet count and LDH are laboratory parameters and are therefore not directly relevant to patients. Furthermore, there is no validation of the incidence of acute cTTP events as a surrogate parameter for patient-relevant endpoints.
  • The occurrence of acute cTTP events may represent an important parameter for treatment management and is presented here for supplementary information.
• quality of life
  • Health-related quality of life was assessed according to age using the SF-36 (Short Form-36 Health Survey) and PedsQL (Pediatric Quality of Life Inventory) instruments.
  • The pharmaceutical manufacturer does not provide any data on health-related quality of life, citing the minor response rates. Across all periods, the response rates for the SF-36 were slightly below 70 per cent and those for the PedsQL were significantly below 70 per cent.
  • Consequently, no data are available and it is not possible to assess the effect of rADAMTS13 on health-related quality of life.
• Side effects – Adverse events (AEs), total
  • In study 281102, an adverse event occurred in 86% of patients in the intervention arm; in the control arm, the figure was 90%. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of rADAMTS13 in the treatment of adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) who are receiving rADAMTS13 as prophylactic treatment, Study 281102 provides results for the endpoint categories of mortality, morbidity and side effects compared with standard of care (SoC).
  • With regard to the endpoint category of mortality, no deaths occurred during the course of the study. The endpoint ‘deaths’ is irreversible and therefore cannot be meaningfully investigated in a crossover study design. The present study design is thus not suitable for comparing the number of deaths between the treatment arms.
  • The analyses presented for the endpoint ‘subacute cTTP events’ within the morbidity endpoint category are considered irrelevant to patients in the present operationalisation, as it could not be demonstrated that every event in the study was associated with a cTTP-specific symptom. According to the present operationalisation, a change in the relevant laboratory parameters alone could be sufficient for an event to be classified as a subacute cTTP event. These laboratory parameters do not constitute patient-relevant endpoints. Furthermore, in the morbidity category for the endpoint ‘neurological symptoms’, the study shows no statistically significant difference between the treatment groups.
  • No data are available regarding health-related quality of life.
  • The results on side effects show a statistically significant difference in favour of rADAMTS13 compared with SoC for the SAE endpoint. Overall, rADAMTS13 is assumed to offer an advantage over SoC. However, the estimation of this advantage is subject to significant uncertainties.
  • On balance, the G-BA classifies the extent of the additional benefit of rADAMTS13 for the treatment of adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) who receive rADAMTS13 as a prophylactic treatment are non-quantifiable, because the scientific evidence does not permit quantification.

b) Adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) who receive rADAMTS13 for acute treatment

• Adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) who receive rADAMTS13 for acute treatment
• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification
• The pharmaceutical manufacturer did not include data on acute treatment from study 281102 in the dossier, as these analyses were deemed to be of limited relevance for the benefit assessment due to the small number of cases (N=6) and the short duration of treatment. This assessment is shared by the G-BA.
• No data are available for the assessment of the additional benefit of rADAMTS13 for the treatment of adults and children with congenital thrombotic thrombocytopenic purpura (cTTP) who receive rADAMTS13 as acute treatment.
• Overall, there is a hint of a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.