Donanemab (1) – Kisunla®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted analyses of the double-blind, randomised, controlled AACI trial.

a) Adults with a clinical diagnosis of mild cognitive impairment resulting from Alzheimer’s disease, who are heterozygous apolipoprotein E ε4 (ApoE ε4) carriers or ApoE ε4 non-carriers, and in whom amyloid pathology has been confirmed

• Best supportive care has been identified as the appropriate comparator therapy for donanemab.
• No suitable data are available for assessing the additional benefit in this patient population, as the study sub-populations submitted by the pharmaceutical manufacturer do not adequately represent patient group a.
• Consequently, there is no evidence of additional benefit from donanemab for the treatment of adults with a clinical diagnosis of mild cognitive impairment due to Alzheimer’s disease who are heterozygous ApoE ε4 carriers or ApoE ε4 non-carriers and in whom amyloidpathology, there is no proof of it.

b) Adults with a clinical diagnosis of mild dementia resulting from Alzheimer’s disease, who are heterozygous apolipoprotein E ε4 (ApoE ε4) carriers or ApoE ε4 non-carriers and in whom amyloid pathology has been confirmed

• Donepezil, galantamine or rivastigmine were identified as appropriate comparator therapies for donanemab.
• In a weighed-up decision, the G-BA concludes that additional benefit from donanemab is not proven for patient group b.
• mortality
  • The findings on overall mortality are based on data on fatal adverse events (AEs). For the endpoint of overall mortality, there is no statistically significant difference between the treatment arms.
• Morbidity – Symptoms assessed using the Clinical Dementia Rating – Sum of Boxes (CDR-SB)
  • Analyses are available for the time to a permanent deterioration in the CDR-SB of at least 2.7 points (corresponding to 15 per cent of the scale range). These are used for the benefit assessment.
  • Based on these analyses, there is no statistically significant difference between the treatment arms in either of the two study sub-populations relevant to patient group b.
• Morbidity – Cognition using the Alzheimer’s Disease Assessment Scale – Cognitive Subscale 13 (ADAS-Cog13)
  • Analyses are available for the time to permanent deterioration in the ADAS-Cog13 by at least 12.75 points (corresponding to 15% of the scale range). These are used for the benefit assessment.
  • For the study subpopulation defined on the basis of the CDR-GS, these analyses show no statistically significant difference between the treatment arms. For the study subpopulation defined on the basis of the CDR-SB, however, a statistically significant advantage of donanemab is observed.
  • Despite the patient populations defined according to CDR-GS and CDR-SB overlapping almost completely, the difference in favour of donanemab is not consistently statistically significant in both patient populations; consequently, the effect is not considered robust. Against this background, there is no difference in the cognition endpoint that is relevant for the benefit assessment.
• Health-related quality of life
  • No QOL-AD assessments were provided for the study subpopulations relevant here. Consequently, no suitable data are available for assessing health-related quality of life.
• Side effects
  • For the overall rates of serious adverse events (SAEs), there is no statistically significant difference between the treatment arms in either of the study subpopulations relevant to patient group b.
  • With regard to the endpoint of therapy discontinuations due to adverse events (AEs), a statistically significant disadvantage of donanemab was observed in both study subpopulations relevant to patient group b.
  • In detail, for the endpoint ‘infusion-related reactions’, a statistically significant disadvantage for donanemab was observed in both study subpopulations relevant to patient group b.
• Overall assessment
  • For the benefit assessment of donanemab for the treatment of adults with a clinical diagnosis of mild dementia due to Alzheimer’s disease, who are heterozygous ApoE ε4 carriers or ApoE ε4 non-carriers and in whom amyloid pathology has been confirmed, data are available based on the AACI study.
  • With regard to mortality, there are no statistically significant differences between the treatment arms.
  • In the morbidity endpoint category, there were no statistically significant differences between the treatment arms for the symptomatic endpoint as measured by the CDR-SB. For the ‘cognition’ endpoint, as measured by ADAS-Cog13, a statistically significant advantage of donanemab was observed in the patient population defined on the basis of the CDR-SB. In the patient population defined on the basis of the CDR-GS, however, no statistically significant difference was observed between the treatment arms. As the difference in favour of donanemab is therefore not consistently statistically significant across both patient populations, the effect is not considered robust. Overall, there is no difference relevant to the benefit assessment for the ‘cognition’ endpoint.
  • No suitable data are available for the sub-populations relevant to the benefit assessment within the health-related quality of life endpoint category.
  • Consequently, there are no differences relevant to the benefit assessment in the endpoint categories of mortality and morbidity. No suitable data are available for the health-related quality of life endpoint category. In the adverse events endpoint category, there is a statistically significant disadvantage of donanemab in terms of therapy discontinuations due to AEs.

Courtesy translation only, please refer to the German original.