Crovalimab (1) – Piasky®

• Clinical trials
  • To demonstrate the additional benefit in patient group a), the pharmaceutical manufacturer has submitted the results of the open-label, randomised, controlled non-inferiority trial COMMODORE 2, which compared crovalimab with eculizumab.
  • To demonstrate additional benefit in patient group b), the pharmaceutical manufacturer has submitted the results of the open-label, randomised COMMODORE 1 trial.

a) Adult and paediatric patients aged 12 years and over with a body weight of ≥ 40 kg and paroxysmal nocturnal haemoglobinuria (PNH) with high disease activity, characterised by clinical symptoms of haemolysis

• The additional benefit is not proven.
• Overall, the additional benefit of Crovalimab compared with Eculizumab for the treatment of adults and paediatric patients aged 12 years and over with a body weight of ≥ 40 kg with paroxysmal nocturnal haemoglobinuria with high disease activity, characterised by clinical symptoms of haemolysis, no proof exists.
• mortality
  • Overall survival was not assessed as an independent endpoint in the COMMODORE 2 study. The results for the endpoint of overall survival are based on data on fatal AEs. There is no statistically significant difference between the treatment groups.
• Morbidity – Transfusion-free status
  • The endpoint ‘transfusion-free status’ was defined in the COMMODORE 2 study as the proportion of patients who did not receive a red blood cell concentrate transfusion from the start of the study until week 25 and who did not require a transfusion in accordance with the guidelines specified in the protocol.
  • No statistically significant difference was observed between the treatment groups for the endpoint of transfusion-free status.
• Morbidity – Severe Adverse Vascular Events (MAVE)
  • No statistically significant difference was observed between the treatment groups for the MAVE endpoint.
• Morbidity – Breakthrough haemolysis
  • The endpoint ‘breakthrough haemolysis’ is therefore not considered patient-relevant in the operationalisation presented; consequently, the available data are deemed unsuitable for drawing conclusions regarding patient-relevant effects.
• Morbidity – Fatigue (FACIT-Fatigue)
  • In the presented responder analyses of clinically relevant improvement, no statistically significant difference was observed between the treatment groups.
• Morbidity – General health status (EQ-5D Visual Analogue Scale)
  • The presented responder analysis on clinically relevant improvement showed no statistically significant difference between the treatment arms.
• Morbidity – Symptoms (EORTC Item List 40; Patient Global Impression of Severity Survey)
  • The isolated use of an item list without the core questionnaire is not appropriate. The EORTC IL40 item list is therefore not used for this assessment.
• Quality of life – EORTC QLQ-C30
  • In accordance with the manual, the EORTC questionnaires are, in principle, validated in their entirety with all scales and must therefore be administered and reported in full. The scales presented do not, therefore, fully reflect health-related quality of life and are not suitable for assessing the additional benefit of Crovalimab.
• Side effects – Total adverse events (AEs)
  • AEs occurred in approximately 77.8% of patients in the intervention arm and in approximately 79.7% of patients in the control arm. The results are presented for supplementary information only.
• Side effects – serious SAEs, severe AEs and therapy discontinuations due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints SAEs, severe AEs and therapy discontinuations due to AEs.
• Overall assessment
  • With regard to patient-relevant endpoints in the categories of mortality, morbidity and side effects, there were neither advantages nor disadvantages for crovalimab compared with eculizumab.
  • No suitable data were provided for the assessment of health-related quality of life.
  • Overall, therefore, there are neither positive nor negative effects of Crovalimab compared with Eculizumab; consequently, no added benefit has been demonstrated for Crovalimab in the treatment of adult and paediatric patients aged 12 years and over with a body weight of ≥ 40 kg who have PNH with high disease activity, characterised by clinical symptoms of haemolysis, additional benefit is not proven.

b) Adults and paediatric patients aged 12 years and over with a body weight of ≥ 40 kg with paroxysmal nocturnal haemoglobinuria (PNH) who have been receiving a C5 inhibitor for ≥ 6 months and are clinically stable

• An additional benefit is not proven.
• On balance, the assessment concludes that the additional benefit of crovalimab over eculizumab for the treatment of adults and paediatric patients aged 12 years and over with a body weight of ≥ 40 kg with paroxysmal nocturnal haemoglobinuria (PNH) who have been receiving a C5 inhibitor for ≥ 6 months and are clinically stable does not have proof.
• mortality
  • In the COMMODORE 1 study, no deaths occurred during the 24-week primary treatment phase. The available data therefore show no relevant difference between the treatment arms.
• Morbidity – transfusion-free status
  • In the COMMODORE 1 study, there was no statistically significant difference between the treatment groups in terms of freedom from transfusion.
• Morbidity – Severe Adverse Vascular Events (MAVE)
  • For the MAVE endpoint, the COMMODORE 1 study showed no statistically significant difference between the treatment groups.
• Morbidity – Breakthrough haemolysis
  • For the reasons outlined above, the endpoint ‘breakthrough haemolysis’ is not considered patient-relevant in the operationalisation presented here; consequently, the available data are deemed unsuitable for drawing conclusions regarding patient-relevant effects.
• Morbidity – Fatigue (FACIT-Fatigue)
  • The endpoint ‘fatigue’ was assessed in the COMMODORE 1 study using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. A statistically significant advantage of crovalimab over eculizumab was observed.
  • The potential for bias in the patient-reported endpoints is assessed as high due to the open-label study design.
• Morbidity – General health status (EQ-5D VAS)
  • In the presented responder analysis of clinically relevant improvement, no statistically significant difference was observed between the treatment arms.
• Morbidity – Symptoms (EORTC IL40)
  • For the reasons outlined above, the EORTC IL40 item list is not used to assess the additional benefit of Crovalimab.
• Quality of life – EORTC QLQ-C30
  • Quality of life was assessed in the COMMODORE 1 study using the physical functioning, role functioning and overall health status/quality of life scales from the EORTC QLQ-C30. For the reasons outlined above, the data presented are not suitable for assessing the additional benefit of Crovalimab.
• Side effects – Total adverse events (AEs)
  • AEs occurred in approximately 79.5% of patients in the intervention arm and in approximately 66.7% of patients in the control arm. The results are presented here for supplementary information only.
• Side effects – Serious AEs (SAEs)
  • No statistically significant difference was observed between the treatment groups for the SADs endpoints.
• Side effects – Severe AEs
  • For the endpoint of severe AEs, there was a statistically significant difference in favor of Crovalimab that was associated with a disadvantage.
• Side effects – Therapy discontinuation due to AEs
  • In the COMMODORE 1 study, there were no therapy discontinuations due to AEs.
• Overall assessment
  • No deaths occurred in the COMMODORE 1 study; consequently, no difference was observed between the treatment groups with regard to the mortality endpoint.
  • With regard to the morbidity endpoint category, an advantage of Crovalimab over Eculizumab was observed for the fatigue endpoint, assessed using the FACIT-Fatigue questionnaire. The potential for bias in the patient-reported endpoints is considered high due to the open-label study design.
  • For the other patient-relevant endpoints in the morbidity category (transfusion-free status, MAVE and general health status, assessed using the EQ-5D VAS), no statistically significant differences were observed between the treatment groups.
  • No suitable data were provided for the assessment of health-related quality of life.
  • With regard to side effects, Crovalimab shows a disadvantage compared with Eculizumab in the endpoint ‘severe AEs’.
  • Overall, an advantage of crovalimab in the ‘fatigue’ endpoint is offset by a disadvantage in the ‘severe AEs’ endpoint.
  • In its decision-making process, the G-BA concludes that, for crovalimab in the treatment of adult and paediatric patients aged 12 years and over with a body weight of ≥ 40 kg who have paroxysmal nocturnal haemoglobinuria, who have been receiving a C5 inhibitor for ≥ 6 months and are clinically stable, an additional benefit over eculizumab is not proven.

Courtesy translation only, please refer to the German original.