[Pharmaceutical Directive/Annex XII: Glucarpidase (reduction of toxic plasma methotrexate concentrations; aged 28 days and older)]

The Federal Joint Committee [Gemeinsamer Bundesausschuss] (G-BA)
Record ID 32018004245
English, German
Original Title: Arzneimittel-Richtlinie/Anlage XII: Glucarpidase (Verringerung toxischer MTX-Plasmakonzentrationen; ab einem Alter von 28 Tagen)
Authors' objectives: The Federal Joint Committee [Gemeinsamer Bundesausschuss (G-BA)] has had the legal task of carrying out an (additional) benefit assessment for all newly approved drugs with new active ingredients immediately after market entry (§ 35a SGB V). The result of this assessment is the basis for deciding how much the statutory health insurance pays for a new drug with a new active ingredient. The G-BA was commissioned to carry out the benefit assessment through the Pharmaceuticals Market Reorganisation Act [Gesetz zur Neuordnung des Arzneimittelmarktes (AMNOG)]. In the context of the early benefit assessment of medicinal products containing new active substances, the following rules apply to orphan drugs: According to the legal requirements (§ 35a SGB V), the additional medical benefit of these drugs is already considered to be proven by the approval. The G-BA determines the extent of the additional benefit for orphan drugs that do not exceed a turnover of 50 million Euros in the last twelve calendar months, on the basis of the approval and the studies justifying the approval.
Authors' results and conclusions: Glucarpidase is used to reduce toxic methotrexate plasma concentrations in adults and children (aged 28 days and older) with delayed elimination of methotrexate, or when there is a risk of methotrexate toxicity. The recommended dose is a single dose of 50 U/kg. The benefit assessment of Glucarpidase is based on pivotal studies PR001-CLN-001, PR001-CLN-002, PR001-CLN-003, PR001-CLN-006 and PR001-CLN-017. Studies 001, 002, 003, and 006 are single-arm compassionate use studies that evaluated the efficacy and safety of Glucarpidase. The primary efficacy endpoint was defined as the proportion of subjects who achieved a clinically relevant reduction (CIR) in plasma MTX concentrations. Study 017 is a non-randomized, two-arm study that evaluated the PK profile of leucovorin in subjects treated with Glucarpidase. In this study, safety of Glucarpidase therapy was surveyed. The dosings in the pivotal studies differ from the recommended dosing according to SmPC. Of 419 subjects in the safety population for whom dosing information was available 30% received doses < 40 U/kg. Furthermore, baseline data showed that many subjects in the pivotal studies received Glucarpidase for whom delayed MTX elimination was not documented. The company presented a target population as a sub-population from the pivotal studies who had received a single dose of Glucarpidase of 50 U/kg (range: 48-52) and for whom a delayed MTX elimination was documented. The target population comprises 124 subjects in the safety population and 55 subjects in the central MTX HPLC population and thus corresponds to approximately 25% of the safety population and 33% of the central MTX HPLC population of the total population of the pivotal studies. There were 11 deaths (8.9%) in the target population within the first 30 days after Glucarpidase administration. 33 of 55 subjects (60%) achieved a CIR. Interpretation of safety results is difficult of the single-arm studies and Glucarpidase-related toxicity may be masked by life-threatening HD-MTX toxicity and underlying oncologic disease. Most of the documented AEs depict common sequelae of HD-MTX treatment or underlying diseases.
Project Status: Completed
Year Published: 2022
Requestor: The Federal Joint Committee [Gemeinsamer Bundesausschuss] (G-BA)
English language abstract: An English language summary is available
Publication Type: Full HTA
Country: Germany
MeSH Terms
  • Methotrexate
  • gamma-Glutamyl Hydrolase
  • Recombinant Proteins
  • Glucarpidase
  • methotrexate
  • toxicity
Organisation Name: The Federal Joint Committee
Contact Address: Gutenbergstr. 13, 10587 Berlin, Germany
Contact Name: Fachberatung Medizin [Department of Medical Consultancy]
Contact Email: Fachberatung-Medizin@g-ba.de
Copyright: https://www.g-ba.de/sys/impressum/
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