Pegcetacoplan (2) – Aspaveli®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the pivotal, completed, multicentre, randomised, controlled, open-label Phase III PRINCE trial for the purpose of benefit assessment.

Adults with paroxysmal nocturnal haemoglobinuria (PNH) who have haemolytic anaemia and have not previously received treatment with a complement inhibitor

• mortality
  • Overall survival was not assessed as a separate endpoint in the PRINCE trial. Deaths were recorded as part of the adverse event monitoring.
  • In the study, one death occurred in each of the two treatment arms.
  • However, due to the uncertainties in the PRINCE study outlined above, the results for the mortality endpoint category cannot be assessed and are therefore not suitable for quantifying the extent of the additional benefit.
• morbidity
  • Stabilisation of the haemoglobin (Hb) level by week 26 and change in the lactate dehydrogenase (LDH) level at week 26
  • The endpoints ‘stabilisation of the haemoglobin (Hb) level’ and ‘change in the lactate dehydrogenase (LDH) level’ were the co-primary endpoints of the PRINCE study.
  • These endpoints represent laboratory parameters with no direct relation to symptoms and are not, in themselves, relevant to patients. As they are co-primary endpoints, they are presented here for the sake of completeness.
  • Transfusion-free status
  • The endpoint ‘transfusion-free status’ describes the proportion of patients who did not receive any transfusions (whole blood, red blood cell concentrates or other blood transfusions) during the 26-week treatment period. In the analyses presented, study participants were classified as transfusion-free provided they had not received a transfusion prior to withdrawal from the study.
  • Many patients in this therapeutic indication require regular transfusions. The long-term or sustained avoidance of transfusions (transfusion-free status or long-term avoidance of transfusions) whilst maintaining a defined minimum haemoglobin level represents a relevant therapeutic goal in this therapeutic indication, enabling the control of anaemia and anaemia-related symptoms whilst avoiding the need for transfusions. Long-term freedom from transfusions may therefore represent a patient-relevant endpoint in this therapeutic indication.
  • There are uncertainties regarding possible differences in transfusion practice, as no information is available on which symptoms were used as transfusion criteria in the PRINCE study and whether these symptoms were predefined.
  • Nevertheless, due to the uncertainties regarding the PRINCE study outlined above, the results on freedom from transfusion cannot be assessed and are therefore not suitable for quantifying the extent of the additional benefit. The endpoint is presented only as supplementary information due to limitations in its operationalisation and validity.
  • Fatigue (FACIT-Fatigue)
  • In the PRINCE study, fatigue was assessed using the FACIT-Fatigue questionnaire and the EORTC QLQ-C30.
  • In the dossier on the FACIT-Fatigue, the pharmaceutical manufacturer presents analyses both as a continuously scaled variable and in the form of time-to-event analyses. For the benefit assessment, the time-to-event analysis of the time to first deterioration was taken into account. In addition to the severity of fatigue symptoms, the FACIT-Fatigue also assesses the impact of these symptoms on functionality in everyday life and during social activities.
  • However, due to the uncertainties of the PRINCE study outlined above, the FACIT-Fatigue results cannot be evaluated and are therefore not suitable for quantifying the extent of the additional benefit.
  • Symptoms (EORTC QLQ-C30)
  • Symptoms were assessed in the PRINCE study using the symptom scales of the EORTC-QLQ-C30 questionnaire.
  • The EORTC QLQ-C30 is a generic measurement tool for assessing symptoms and quality of life in patients with oncological diseases. The relevance of individual items in the questionnaire to the symptoms in the present therapeutic indication is unclear. The symptom scales of the EORTC QLQ-C30 are therefore not used for this assessment.
  • Nevertheless, due to the uncertainties in the PRINCE study outlined above, the results on symptoms cannot be assessed and are therefore not suitable for quantifying the extent of the additional benefit.
• quality of life
  • EORTC QLQ-C30
  • Data on health-related quality of life from the PRINCE study are available based on the functional scales and the global health status scale of the EORTC QLQ-C30.
  • The pharmaceutical manufacturer provides analyses for the time to improvement and deterioration. For the present assessment, the event time analysis for ‘time to first deterioration’ without censoring following a crossover is considered the appropriate analysis in the context of the study design selected here. This is justified, amongst other things, by the fact that for relevant PROs, a deterioration may occur prior to a change in treatment, and any improvements in symptoms or quality of life following a crossover have no influence on the analysis. Furthermore, in the ‘time to first deterioration’ event time analyses, more participants were followed for longer than in the ‘time to first improvement’ analyses.
  • LASA
  • In the PRINCE study, further data on health-related quality of life were collected using the Linear Analogue Scale Assessment (LASA). Due to the lack of validation of the overall LASA score, the individual scales are used for the benefit assessment.
  • Nevertheless, the results for the quality of life endpoint category cannot be assessed due to the uncertainties in the PRINCE study outlined above and are therefore not suitable for quantifying the extent of the additional benefit.
• Side effects
  • Total adverse events (AEs)
  • In the PRINCE study, AEs occurred in approximately 80% of patients in the intervention arm and approximately 67% of patients in the comparator arm. The results are presented here for supplementary information only.
  • Serious AEs (SAEs), severe AEs
  • Isolated cases of severe AEs and SAEs occurred in both treatment arms.
  • Therapy discontinuations due to AEs
  • No patients experienced therapy discontinuation due to AEs.
  • Nevertheless, the results for the ‘side effects’ endpoint category cannot be assessed due to the uncertainties of the PRINCE study outlined above and are therefore not suitable for quantifying the extent of the additional benefit.

Courtesy translation only, please refer to the German original.