Vadadustat (1) – Vafseo®

• Clinical trials
  • Both studies are open-label, multicentre, parallel-group RCTs comparing vadadustat with darbepoetin alfa.

Adults with symptomatic anaemia resulting from chronic kidney disease (CKD) who are receiving chronic maintenance dialysis

• An additional benefit is not proven.
• mortality
  • For the endpoint ‘all-cause mortality’, the meta-analysis of studies CI-0016 and CI-0017 shows no statistically significant difference between the treatment arms.
• Morbidity – freedom from transfusion
  • In its dossier, the pharmaceutical manufacturer provides analyses of transfusion-free status at week 52. However, these analyses do not take into account data collected after patients experienced therapy discontinuation.
  • As part of the written commenting procedure, the pharmaceutical manufacturer has submitted analyses of the proportion of patients who did not receive a red blood cell transfusion from the start of the study until its end.
  • As previously stated, red blood cell transfusions for the treatment of symptomatic anaemia resulting from chronic kidney disease are recommended only as a secondary option, particularly due to the risk of alloimmunisation and the potential complications this may cause in the event of a subsequent kidney transplant.
  • Against this background, the endpoint of ‘transfusion-free status’ is not used to derive any additional benefit.
• health-related quality of life
  • No health-related quality of life endpoints were assessed in studies CI-0016 and CI-0017.
• Side effects – serious adverse events (SAEs)
  • For the SAE endpoint, the meta-analysis of studies CI-0016 and CI-0017 shows a statistically significant advantage of vadadustat over darbepoetin alfa.
  • It should be noted here that there are uncertainties regarding the authorised dosage of darbepoetin alfa in the comparator arm, which could not be resolved even by the additional information subsequently provided by the pharmaceutical manufacturer.
• Side effects – discontinuation due to adverse events (AE)
  • For the endpoint ‘discontinuation due to AEs’, the meta-analysis of studies CI-0016 and CI-0017 shows a statistically significant disadvantage of vadadustat compared with darbepoetin alfa.
• Side effects – Major Adverse Cardiovascular Events (MACE), hospitalisation due to heart failure and thromboembolic events
  • For the endpoints MACE (comprising the individual components of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke), hospitalisation due to heart failure, and thromboembolic events (comprising the individual components of arterial thrombosis, deep vein thrombosis, pulmonary embolism and vascular access thrombosis), the meta-analysis of studies CI-0016 and CI-0017 showed no statistically significant difference between the treatment arms in any of these cases.
• Side effects – liver toxicity
  • For the endpoint of liver toxicity, the meta-analysis of studies CI-0016 and CI-0017 shows no statistically significant difference between the treatment arms.
• Side effects – Specific AEs
  • In detail, the meta-analysis of studies CI-0016 and CI-0017 shows a statistically significant advantage of vadadustat over darbepoetin alfa for the specific adverse events ‘cardiac disorders (SOC, SAE)’, ‘benign, malignant and unspecified neoplasms (SOC, SAE)’, ‘urinary tract infection (PT, SAE)’ and ‘altered mental state (PT, SAE)’, the meta-analysis of studies CI-0016 and CI-0017 showed a statistically significant advantage of vadadustat over darbepoetin alfa in each case.
• Overall assessment
  • An overall review of the results thus reveals statistically significant differences between the treatment arms exclusively in terms of side effects.
  • As both positive and negative effects of the active ingredient vadadustat occur in this endpoint category, no additional benefit of vadadustat over darbepoetin alfa is identified in the overall assessment.

Courtesy translation only, please refer to the German original.