Belatacept (2) – Nulojix®

• Clinical trials
  • In its dossier, the pharmaceutical manufacturer presented the results of the two randomised controlled trials, BENFIT (IM103008) and BENEFIT-EXT (IM103027), to address the research question.

Adults who have undergone a kidney transplant, for the prevention of graft rejection in combination with corticosteroids and mycophenolic acid (MPA)

• For the prevention of graft rejection in combination with corticosteroids and mycophenolic acid in adults who have undergone a kidney transplant, there is an indication of a considerable additional benefit compared with the appropriate comparator therapy, ciclosporin in combination with corticosteroids and mycophenolate mofetil.
• Overall, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA concludes that there is an indication of considerable additional benefit from belatacept (in combination with corticosteroids and mycophenolate mofetil) compared with ciclosporin A (in combination with corticosteroids and mycophenolate mofetil).
• mortality
  • Overall mortality
  • Due to an indication of heterogeneity (I = 66.2%; tau = 0.159; p = 0.085), the results were analysed at the level of individual studies.
  • Neither study showed a statistically significant difference between the treatment groups (BENEFIT study: HR: 0.55, 95% CI: [0.3; 1.04]; p = 0.062; BENEFIT-EXT study: HR: 1.10, 95% CI [0.68; 1.80]; p = 0.1692).
  • An additional benefit of belatacept compared with the appropriate comparator therapy, ciclosporin A, is therefore not proven for the endpoint of mortality.
• Morbidity – Graft loss
  • For the endpoint of graft loss, no statistically significant difference was observed between belatacept and the appropriate comparator therapy (HR: 0.67, 95% CI [0.43; 1.04]; p = 0.076).
  • Consequently, there is no additional benefit of belatacept over the appropriate comparator therapy, ciclosporin A, for the endpoint of graft loss.
• Morbidity – Death or Graft Loss
  • The results for the composite endpoint ‘death or graft loss’ were analysed at the individual study level due to an indication of heterogeneity (I = 56.5%; tau = 0.065; p = 0.13).
  • In contrast, for patients with an ECD transplant (BENEFIT-EXT study), no statistically significant difference was observed between belatacept and the appropriate comparator therapy, ciclosporin A (HR: 0.92, 95% CI [0.63; 1.35]; p = 0.670).
  • The overall conclusion regarding additional benefit remains unaffected by this, as there is an overall indication of considerable additional benefit.
• Morbidity – Cardiovascular morbidity and mortality
  • For the combined endpoint of ‘cardiovascular morbidity and mortality’, no statistically significant difference was observed between belatacept and the appropriate comparator therapy (HR: 0.86, 95% CI [0.52; 1.41]; p = 0.555).
  • Consequently, there is no additional benefit of belatacept over the appropriate comparator therapy, cyclosporine A, for this endpoint.
• Morbidity – Cardiorenal morbidity and mortality
  • For the combined endpoint of ‘cardiorenal morbidity and mortality’, there was no statistically significant difference between belatacept and the appropriate comparator therapy (HR 0.83, 95% CI [0.62; 1.11]; p = 0.215).
  • Consequently, there is no additional benefit of belatacept over the appropriate comparator therapy, cyclosporine A, for this endpoint.
• Morbidity – Renal insufficiency in Chronic Kidney Disease (CKD) stages 4/5
  • Analysis of the results on renal function (cGFR) shows that, using the Chronic Kidney Disease (CKD) classification, that after a treatment duration of 84 months, there was a statistically significantly lower proportion of patients with CKD stage 4 or 5 renal insufficiency in the belatacept treatment group than in the group receiving the appropriate comparator therapy (BENEFIT study: HR: 0.44, 95% CI [0.32; 0.62]; p < 0.001; BENEFIT-EXT study: HR: 0.60, 95% CI [0.46; 0.78]; p < 0.001; overall: RR: 0.58, 95% CI [0.43; 0.78]; p < 0.001).
  • In both studies, effects of a similar magnitude and in the same direction were observed, such that, despite an indication of heterogeneity (I = 51.5%; tau = 0.025; p = 0.151), it is possible to interpret the results for patients with SCD and ECD transplants collectively.
  • For this endpoint, belatacept demonstrates a considerable additional benefit, independent of donor type, compared with the appropriate comparator therapy, ciclosporin A.
• Health-related quality of life
  • No quality of life data were collected at month 84.
  • Consequently, no usable data on quality of life are available for the time point on which the assessment is based.
  • The data on quality of life available at month 60 do not relate to the intention-to-treat (ITT) population and are therefore also unsuitable for assessing the additional benefit of belatacept for this endpoint; it should also be noted that no additional benefit of belatacept with regard to quality of life could be inferred from the data for month 36 either (see resolution on belatacept of 5 July 2012).
  • An additional benefit or less benefit of belatacept with regard to quality of life is not proven overall.
• Side effects – severe adverse events (SAEs)
  • The results on SAE, based on the survival time analyses to account for the varying observation periods as set out in the pharmaceutical manufacturer’s written submission, were examined at the individual study level due to proof of heterogeneity at month 84 (Q = 3.93: df = 1; p = 0.048; I = 74.5%).
  • Based on the results of the BENEFIT study at month 84, a statistically significant difference was observed between the treatment groups in favour of belatacept for patients with SCD transplants compared with ciclosporin A (HR: 0.74, 95% CI [0.60; 0.93]; p = 0.008).
  • For patients with an ECD transplant, however, the BENEFIT-EXT study showed no statistically significant difference (HR: 1.02 [0.82; 1.27]; p = 0.870).
  • This does not affect the overall conclusion regarding additional benefit, as there is an indication of considerable additional benefit overall.

Courtesy translation only, please refer to the German original.