Eftrenonacog alfa (1) – Alprolix®

• Clinical trials
  • The open-label, multicentre trials B-LONG, Kids B-LONG and B-YOND were included in the assessment of additional benefit.
  • The B-LONG study included 123 male patients aged 12 years and over with haemophilia B and ≤ 2 % endogenous FIX activity, who had previously been treated with a recombinant or human plasma-derived factor IX preparation.
  • The Kids-B-LONG study included 15 children under 6 years of age and 15 children aged 6 to under 12 years with severe haemophilia B.
  • The B-YOND study included patients who had previously participated in the B-LONG, Kids-B-LONG or any other study with eftrenonacog alfa.

Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency)

• In summary, the additional benefit of eftrenonacog alfa is assessed as follows: there is a non-quantifiable additional benefit.
• mortality
  • No events occurred in the mortality category.
• morbidity
  • The related endpoints concerning factor consumption (‘FIX consumption in prophylaxis’, ‘number of infusions per month’, ‘dose per infusion’) are not considered, in themselves, to be relevant to patients and are not used to draw conclusions regarding the extent of the additional benefit.
  • Should these factors be relevant to patients, this should be reflected both in the endpoint categories of safety and quality of life, as well as in the bleeding rate.
• quality of life
  • To measure quality of life, the Haemo-QoL and Heam-A-QoL questionnaires were used in the B-LONG study, and the CHO-KLAT questionnaire was used in the Kids-B-LONG study.
  • No results for the Haemo-QoL and Heam-A-QoL are available from the B-YOND study.
  • In the B-LONG study, too few patients completed the Haemo-QoL questionnaire, meaning that no valid data on this questionnaire are available from this study.
  • From the B-LONG study, information on quality of life assessed using the Haem-A-QoL was available for 26 patients from study arm 1 (n=33, weekly dose-optimised prophylaxis) and for 13 patients from study arm 2 (n=15, individualised interval prophylaxis).
  • A change in the Haem-A-QoL score over time was considered clinically relevant if it was greater than the highest response threshold in the range; it was considered potentially clinically relevant if the change fell within the range of response thresholds; and a change was considered clinically irrelevant if it was less than the lowest response threshold in the range.
  • For patients in study arm 1 (weekly dose-optimised prophylaxis), the median change from baseline in the total Haem-A-QoL score was –6.82 at week 26 and –5.60 at week 52.
  • For more than half of the study participants, this change can be classified as a potentially clinically relevant improvement in quality of life.
  • In study arm 2 (individualised interval prophylaxis), the median change from baseline at week 26 was -5.83.
  • At week 52, the change was below the clinical relevance threshold for more than half of the study participants.
  • For the domains ‘Physical Health’ and ‘Sport and Leisure’, the response threshold for the median change from baseline is -10.00.
  • Although a clinically relevant or potentially clinically relevant change from baseline was observed at week 26 for some participants in study arms 1 and 2, the values at week 52 were below the clinical relevance threshold in both domains and in both study arms for more than half of the study participants.
  • Valid conclusions regarding quality of life cannot therefore be drawn from the minor response rate.
  • In the Kids-B-LONG study, quality of life was assessed using the CHO-KLAT.
  • However, no change in quality of life was observed; according to the carers’ assessment, quality of life actually deteriorated slightly over the course of the study.
  • It is not possible to assess the clinical relevance of this change due to the lack of a response threshold.
• Side effects
  • Endpoints in the ‘side effects’ category were recorded in all the studies presented.
  • Nasopharyngitis was one of the most frequently reported AEs across all studies.
  • No allergic reactions or thrombotic events classified as SAEs occurred in any of the studies.
  • No participants developed inhibitory antibodies.
  • However, the conclusions relate to pre-treated patients, who have a lower risk of developing inhibitory antibodies than treatment-naive patients.
  • Untreated patients have not yet been studied.
  • In the B-LONG study, non-neutralising antibodies against eftrenonacog alfa were detected at baseline in 3 out of a total of 121 patients, and developed in a further patient during the course of the study.
  • In the Kids-B-LONG study, non-neutralising antibodies were detected at baseline in only one patient.
  • Non-neutralising antibodies can lead to immune responses, some of which may be severe, and may indicate the immunogenic potential of the active ingredient (INN).
  • However, no conclusions can be drawn as to the extent to which antibody formation is comparable to that seen with other FIX preparations.
  • No conclusions regarding the extent of the additional benefit can be drawn from the results on side effects.
• Conclusion
  • No conclusions regarding the extent of the additional benefit of eftrenonacog alfa can be drawn from the results on mortality, morbidity, quality of life and side effects in the studies presented.
  • Should these factors be relevant to patients, this should be reflected both in the endpoint categories of safety and quality of life, as well as in the bleeding rate, which are used for the benefit assessment.
  • Given the severity of the condition, an intravenous injection every 2 to 3 days may potentially represent a reduction in quality of life for certain patient groups, particularly children.
  • However, in the studies presented, the reduction in the required frequency of injections did not provide evidence of a clinically relevant improvement in quality of life.

Courtesy translation only, please refer to the German original.