Concizumab (2) – Alhemo®

• Clinical trials
  • The Explorer7 study is the pivotal, open-label, multicentre, partially randomised Phase III trial comprising a main phase and an extension phase with two randomised and two non-randomised arms.

a) Adults and adolescents aged 12 years and over with haemophilia B (congenital factor IX deficiency) and factor IX inhibitors, with an indication for routine prophylaxis, for whom on-demand treatment with bypassing agents alone (human plasma fraction enriched with factor VIII inhibitor-bypassing activity or eptacog alfa) constitutes the appropriate therapy for the individual patient

• Hint of a considerable additional benefit.
• Overall, there is a hint of considerable additional benefit of concizumab compared with on-demand treatment with bypassing agents.
• mortality
  • In the Explorer7 study, two patients in the concizumab arm and no patients in the control arm died. There is no statistically significant difference between the treatment arms.
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment groups.
• Morbidity – Annualised bleeding rates (ABR) and complete freedom from bleeding
  • The number of treated traumatic and spontaneous bleeding episodes is the primary endpoint of the Explorer7 study.
  • For the endpoints of complete freedom from bleeding, treated bleeds and treated joint bleeds, Concizumab demonstrated a statistically significant advantage over on-demand treatment with bypassing agents in each case.
  • In the morbidity endpoint category, a statistically significant advantage of Concizumab over on-demand treatment with bypassing agents is evident in the endpoints of complete freedom from bleeding, treated bleeds and treated joint bleeds.
• Morbidity – Symptoms/Health Status
  • The following patient-reported outcomes (PROs) were collected for the endpoints assessing symptoms and health status: Patient Global Impression of Change (PGI-C), Patient Global Impression of Severity (PGI-S) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v2.0.
  • Due to minor response rates for the PGI-S and PROMIS even at baseline, and the inappropriate non-responder imputations carried out for the PGI-C, the results cannot be used for the present assessment.
  • No suitable data are available for the endpoint ‘symptoms’.
• Health-related quality of life
  • The following patient-reported outcomes (PROs) were collected for the endpoints assessing health-related quality of life: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia Treatment Experience Measure (Hemo-TEM) and Short Form-36 Health Survey Version 2 (SF-36v2).
  • Due to minor response rates for all PROs even at baseline, the results cannot be used for the present assessment.
  • No suitable data were presented in the health-related quality of life endpoint category.
• Side effects
  • For the patient-relevant endpoints of serious adverse events (SAEs) and discontinuation due to AEs, there were no statistically significant differences between the treatment arms.
  • In the ‘side effects’ category, there were no statistically significant differences between the treatment arms for the endpoints ‘SAEs’ and ‘withdrawal due to AEs’.
• Overall assessment
  • For the benefit assessment of Concizumab for the treatment of adults and adolescents aged 12 years and over with haemophilia B (congenital factor IX deficiency) and factor IX inhibitors, with an indication for routine prophylaxis, for whom on-demand treatment with bypassing agents (human plasma fraction enriched with factor VIII inhibitor-bypassing activity or eptacog alfa) is an option, results from the Explorer7 study are available for the endpoint categories of mortality, morbidity, quality of life and side effects, compared with on-demand treatment with bypassing agents.
  • Overall, for concizumab in adults and adolescents aged 12 years and over with haemophilia B and factor IX inhibitors, for whom on-demand treatment with bypassing agents is an option, an additional benefit can be inferred on the basis of the positive effects observed in the morbidity endpoints, the extent of which is classified as considerable.
• Confidence in the findings (probability of additional benefit)
  • This assessment is based on the results of the open-label, multicentre, partially randomised Phase III Explorer7 trial.
  • Due to the lack of temporal parallelism between the two study arms, the potential for bias is classified as high at the study level and for the results of all endpoints.
  • An hint of certainty is therefore assigned to the observed additional benefit.

b) Adults and adolescents aged 12 years and over with haemophilia B (congenital factor IX deficiency) and factor IX inhibitors who have an indication for routine prophylaxis, for whom on-demand treatment with bypassing agents alone (human plasma fraction enriched with factor VIII inhibitor-bypassing activity or eptacog alfa) does not constitute the appropriate therapy for the individual patient

• The additional benefit is not proven.
• Overall, it is therefore concluded that for concizumab in adults and adolescents aged 12 years and over with haemophilia B and factor IX inhibitors who have an indication for routine prophylaxis, and for whom on-demand treatment with bypassing agents is not an option, an additional benefit is not proven.
• For adults and adolescents aged 12 years and over with haemophilia B (congenital factor IX deficiency) and factor IX inhibitors who have an indication for routine prophylaxis, and for whom on-demand treatment with bypassing agents (such as a human plasma fraction enriched with factor VIIIinhibitor-bypassing activity) is not an option, no data are available to demonstrate additional benefit.

Courtesy translation only, please refer to the German original.