Donidalorsen (1) – Dawnzera®

• Clinical trials
  • The OASIS-HAE study is a double-blind, randomised study comparing donidalorsen at two different dosing intervals (monthly and every 2 months) with placebo in people aged 12 years and over with HAE type I or HAE type II.
  • The APeX-2 and APeX-J studies are double-blind, randomised studies of berotralstat in individuals aged 12 years and over with type I or type II HAE.

Adults and adolescents aged 12 years and over with recurrent attacks of hereditary angioedema with an indication for routine prophylaxis

• For adults and adolescents aged 12 years and over with recurrent attacks of hereditary angioedema, with an indication for routine prophylaxis, there is a hint of a minor additional benefit.
• As the results are based on an adjusted indirect comparison, the overall certainty of the findings is limited. There is a hint of a minor additional benefit.
• mortality
  • The findings on overall mortality are based on data on fatal adverse events (AEs). No deaths occurred in any of the OASIS-HAE, APeX-2 or APeX-J studies.
• Morbidity – HAE attacks
  • The occurrence of HAE attacks was recorded in the OASIS-HAE study using the diary-style Angioedema Activity Score (AAS) questionnaire and in the APeX-2 and APeX-J studies via entries made by patients in an electronic diary.
  • For the endpoint ‘monthly rate of HAE attacks’, the adjusted indirect comparison showed a statistically significant difference in favour of donidalorsen compared with berotralstat.
  • For the operationalisation of ‘attack-free status’, which defines the proportion of participants without HAE attacks during the treatment phase, there were no statistically significant differences between donidalorsen and berotralstat.
• Morbidity – Activity impairment (assessed using the WPAI)
  • The patient-relevant endpoint ‘activity impairment’ was assessed in the OASIS-HAE study using question 10 of the Work Productivity and Activity Impairment (WPAI) PLUS Classroom Impairment Questions: specific health problem (CIQ:SHP), and in the APeX-2 and APeX-J studies using question 6 of the WPAI.
  • There was no statistically significant difference for the endpoint ‘activity impairment’.
• Morbidity – Health Status (EQ-5D Visual Analogue Scale)
  • Health status was assessed in the studies using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference was observed for the health status endpoint.
• Quality of life – Angioedema Quality of Life (AE-QoL)
  • The AE-QoL is a disease-specific instrument for assessing the quality of life of adults with recurrent angioedema.
  • For the health-related quality of life endpoint assessed using the AE-QoL, the adjusted indirect comparison revealed a statistically significant advantage for donidalorsen compared with berotralstat for the AE-QoL total score. However, the 95% confidence interval for the standardised mean difference (SMD) does not lie entirely outside the non-significant range of –0.2 to 0.2, so it cannot be concluded that the effect is clinically relevant.
• Side effects – serious AEs (SAEs) and discontinuation due to AEs
  • For the endpoints of SAE and discontinuation due to AEs, the adjusted indirect comparison showed no statistically significant difference between donidalorsen and berotralstat in either case.
• Side effects – Severe AEs
  • No suitable operationalisation is available for the endpoint ‘severe AEs’ in the OASIS-HAE study.
  • Consequently, no suitable data are available for the endpoint ‘severe AEs’ in the adjusted indirect comparison of donidalorsen versus berotralstat.
• Overall assessment
  • Results from an adjusted indirect comparison are available for the assessment of the additional benefit of donidalorsen for use in the routine prevention of recurrent attacks of hereditary angioedema (HAE).
  • Only patients with HAE types I and II were included in the study. Consequently, no conclusions can be drawn regarding the additional benefit in patients with HAE type III.
  • In the mortality category, no deaths occurred in the studies considered.
  • In the morbidity category, for the endpoint ‘HAE attacks’, all confirmed HAE attacks were taken into account, regardless of severity or location. When operationalised as the ‘monthly rate of HAE attacks’, there is a statistically significant advantage of donidalorsen over berotralstat. For the further operationalisation ‘attack-free status’, which defines the proportion of individuals without HAE attacks during the treatment phase, there were no statistically significant differences between donidalorsen and berotralstat.
  • For the other endpoints in the morbidity category – ‘impairment of activity’ (assessed using the WPAI) and ‘health status’ (assessed using the EQ-5D VAS) – no statistically significant difference was observed in either case.
  • In the health-related quality of life category, assessed using the disease-specific Angioedema Quality of Life (AE-QoL) questionnaire, the adjusted indirect comparison revealed no clinically relevant difference between donidalorsen and berotralstat.
  • In the ‘side effects’ category, the adjusted indirect comparison showed no statistically significant difference between donidalorsen and berotralstat for the endpoints of SAE and discontinuation due to AEs.
  • An advantage was observed for donidalorsen in terms of reducing the monthly rate of HAE attacks. No advantages were observed in other morbidity endpoints, such as general health status or health-related quality of life. Overall, the extent of the additional benefit is assessed as minor.

Courtesy translation only, please refer to the German original.