Glucarpidase (1) – Voraxaze®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted data from the four prospective, open-label, non-randomised, multicentre, single-arm compassionate use studies PR001-CLN-001, -002, -003 and -006, and an open-label, non-randomised, multicentre pharmacokinetic (PK) study -017 for the benefit assessment.

Adults, adolescents and children aged 28 days and over with delayed excretion of methotrexate (MTX) or where there is a risk of MTX toxicity

• Hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• In summary, for glucarpidase to reduce toxic MTX plasma concentrations in adults, adolescents and children aged 28 days and over with delayed excretion of methotrexate (MTX) or where there is a risk of MTX toxicity, a hint of non-quantifiable additional benefit is derived, as the scientific evidence does not permit quantification.
• mortality
  • Fatalities were recorded in studies 001, 002, 003, 006 and 017 as part of the safety analysis (safety population). In the studies, 11 deaths occurred up to and including 30 days after glucarpidase treatment (approximately 9% of patients in the pooled target population).
  • The study documentation does not provide sufficient operationalisation for the further recording of deaths beyond day 30, and it remains unclear whether, and over what period, the patients included in the studies were followed up.
• Morbidity – Clinically relevant reduction (CIR) in MTX concentration
  • In studies 001, 002, 003 and 006, a clinically relevant reduction was defined as an MTX concentration of ≤ 1 μmol/l (measured by HPLC) and retrospectively designated as the primary endpoint for all studies.
  • In accordance with the definition in the studies, the endpoint was considered to have been achieved if, following administration of glucarpidase, a MTX concentration in plasma or serum of ≤ 1 μmol/l was reached. All subsequent plasma or serum samples also had to be ≤ 1 μmol/l, meaning that, conversely, there was no renewed rise in the MTX concentration to > 1 μmol/l (a so-called ‘rebound’).
  • In the sensitivity analysis, approximately 60% of patients achieved a CIR in their MTX concentration following treatment with glucarpidase.
  • On a median basis, patients in the pooled target population achieved CIR after 0.25 h (or, on average, after approximately 32 h). As it is unclear what clinical significance the endpoint ‘time to achieve CIR’ has, or what conclusions it allows regarding the patients’ subsequent clinical course, this endpoint is presented solely as supplementary information.
• Morbidity – Change in MTX concentration and change in sCr levels
  • Both MTX and sCr concentrations are laboratory parameters and are not, in themselves, relevant to patients. Therefore, the endpoints ‘change in MTX concentration’ and ‘change in sCr levels’ are not used for the benefit assessment.
• Morbidity – Rebound in MTX concentration
  • A rebound in MTX concentration in patients who had reached a threshold defined as clinically relevant is already indirectly covered by the presentation of the primary endpoint in studies 001, 002, 003 and 006, ‘CIR of MTX concentration’, as this endpoint only included patients who, after reaching the threshold value of ≤ 1 μmol/l, were also able to maintain this level. Against this background, the endpoint ‘rebound in MTX concentration’ is not used for the benefit assessment.
• Health-related quality of life
  • No data on quality of life were collected.
• Overall review
  • In the overall assessment, glucarpidase is found to provide a non-quantifiable added benefit for the reduction of toxic MTX plasma concentrations in adults, adolescents and children aged 28 days and over with delayed excretion of methotrexate (MTX) or where there is a risk of MTX toxicity, as the scientific evidence does not permit quantification of the additional benefit.

Courtesy translation only, please refer to the German original.