Albutrepenonacog alfa (1) – Idelvion®

• Clinical trials
  • The assessment of additional benefit is based on the studies forming the basis for marketing authorisation: CSL654_2004 (Phase I/II), 3001 (pivotal Phase II/III) and 3002 (single-arm, paediatric Phase III), as well as an interim analysis of the currently ongoing extension study 3003.
  • These are open-label, multicentre, uncontrolled trials in which previously treated male haemophilia B patients (≤ 2 % endogenous factor IX(FIX) activity) were treated with albutrepenonacog alfa for prophylaxis and on-demand treatment.

Patients with haemophilia B (congenital factor IX deficiency)

• In summary, the additional benefit of albutrepenonacog alfa is assessed as follows: for patients with haemophilia B, there is a non-quantifiable additional benefit.
• Due to the methodological limitations of the study and the overall limited evidence base, the G-BA classifies the extent of the additional benefit for albutrepenonacog alfa, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing, as non-quantifiable.
• mortality
  • No events occurred in the mortality category.
• morbidity
  • Bleeding events are clinically relevant depending on their extent and frequency. The morbidity endpoint ‘occurrence of bleeding: annualised bleeding rate (ABR)’ was assessed on the basis of bleeding events requiring treatment, with a view to preventing bleeding.
  • The ABR data collected (total ABR, AsBR, annualised joint bleeding rate) in the prophylaxis setting are characterised by high inter-patient variability for children, adolescents and adults alike: For adults, the median (min; max) for the ‘total ABR’ endpoint in the 7-day dosing interval ranges from 0 (0.0; 6.0) [Study 3001] and 2.3 (0.0; 14.0) [Study 2004]. For children < 12 years of age, a median (min; max) total ABR of 3.1 (0.0; 10.7) was determined over the 7-day dosing interval [Study 3002, n=27].
  • It is not possible to assess whether these differences reflect patient-specific characteristics (severity of disease) or represent treatment effects. No reliable conclusions regarding the extent of the additional benefit can be drawn from the morbidity results.
  • The operationalisation and clinical relevance of the bleeding events recorded in the studies—which the pharmaceutical manufacturer classified as not requiring treatment—are unclear.
• quality of life
  • Quality of life was not assessed for the population of adults and adolescents in the studies.
  • To assess quality of life in children aged 4 years and over, the Haemo-QoL questionnaire, in its age-specific version, was used in study 3002. In children aged 8–12 years (n=7), the median Haemo-QoL score (TTS) increased by 5.7 percentage points from baseline to the end of the study, with a very wide range of individual changes [min –18.6; max 1.8], which suggests a slight overall improvement in quality of life.
  • In contrast, in the patient population of 4- to 7-year-old study participants (n=10), a median increase of 4.7 percentage points in the Haemo-QoL TTS was observed; however, given the range [min -23.1; max 25.0], this cannot be interpreted as either an improvement or a deterioration.
  • Due to a lack of information on the clinical relevance threshold for the score, no conclusions can be drawn regarding the clinical relevance of the improvement. No statistical testing of the change at the start of the study was carried out. Overall, therefore, no conclusion can be drawn regarding the extent of the additional benefit in the quality of life category.
• Side effects
  • Endpoints in the ‘Side effects’ category were recorded in all the studies submitted. The most frequently reported AEs across all studies include nasopharyngitis, headache and arthralgia.
  • AE of particular interest (thromboembolism and/or catheter-associated thrombosis, infections at the catheter insertion site, and the occurrence of FIX inhibitors and antibodies against the active ingredient (INN)) did not occur in the underlying studies 3001, 3002 and 3003.
  • In study 2004, antibodies against the CHO host cell protein were not recorded. In general, too few patients were included in the studies to detect rare events such as the occurrence of inhibitors. In summary, no conclusions regarding the extent of the additional benefit can be drawn from the results relating to side effects.
• Conclusion
  • No conclusions regarding the extent of the additional benefit of albutrepenonacog alfa can be drawn from the results on mortality, morbidity, quality of life and side effects in the studies presented.
  • 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.