Belimumab (2) – Benlysta®

• Clinical trials
  • To assess the additional benefit of belimumab in patients aged 5 years and over with active, autoantibody-positive systemic lupus erythematosus (SLE) who exhibit high disease activity despite standard therapy, the pharmaceutical manufacturer submitted the multi-centre, randomised, double-blind, placebo-controlled Phase III PLUTO trial, which formed the basis for marketing authorisation.
  • The PLUTO study is a double-blind RCT comparing belimumab plus individualised concomitant medication versus placebo plus individualised concomitant medication.

Children and adolescents aged 5 to 17 years with active, autoantibody-positive systemic lupus erythematosus (SLE) who exhibit high disease activity despite standard therapy

• mortality
  • No deaths occurred in the PLUTO study.
• Morbidity – Severe flares according to the SELENA-SLEDAI SLE Flare Index (SFI)
  • The prevention of flares in the treatment of SLE is clinically relevant.
  • The endpoint in the ‘morbidity’ category, ‘Severe flares according to SFI’, was defined in the PLUTO study as the occurrence of one of several components; these also include components that lead to events as a result of implementing the appropriate comparator therapy.
  • Any necessary optimisation of treatment, as a possible implementation of the appropriate comparator therapy, is therefore counted as an adverse event (flare).
  • The operationalisation chosen by the pharmaceutical manufacturer for the endpoint ‘Severe relapses according to SFI’ is regarded as critical for the benefit assessment, as an increase in the dose of antimalarial drugs and the addition of NSAIDs were also classified as severe relapses.
  • The analysis chosen by the pharmaceutical company, which includes any treatment adjustment and changes in the SELENA-SLEDAI score, shows a statistically significant difference in favour of belimumab.
  • Against the backdrop of these results and uncertainties, it remains questionable whether an advantage can be inferred from this.
• Morbidity – SLE Responder Index, physical functioning assessed using PedsQL, symptoms assessed using PedsQL
  • In the PLUTO study, the following patient-relevant endpoints in the morbidity category were assessed, amongst others: SLE Responder Index, physical functioning as measured by PedsQL, symptoms as measured by PedsQL, and severe flares according to the SELENA-SLEDAI SLE Flare Index (SFI).
  • The results for the endpoints in the morbidity categories – SLE Responder Index, physical functioning as measured by PedsQL, symptoms as measured by PedsQL, severe flares according to the SFI, and the PedsQL endpoint in the health-related quality of life category cannot be conclusively interpreted in each case due to the nature of the analyses carried out by the pharmaceutical manufacturer.
• Health-related quality of life
  • Health-related quality of life was assessed in the PLUTO study using PedsQL.
  • The results for the endpoints in the categories of SLE Responder Index morbidity, physical functioning as measured by PedsQL, symptoms using the PedsQL, severe flares according to the SFI, and the PedsQL endpoint in the health-related quality of life category cannot be conclusively interpreted in each case due to the nature of the analyses carried out by the pharmaceutical manufacturer.
• Side effects
  • For the endpoint ‘serious adverse events’ (SAE), the PLUTO study identified a statistically significant advantage of belimumab plus patient-specific concomitant medication compared with placebo plus patient-specific concomitant medication, which is considered to have a considerable extent.
  • No patient discontinued treatment with belimumab plus individualised concomitant medication in the PLUTO study. In the comparator arm, one patient discontinued treatment with placebo plus individualised concomitant medication due to an AE. No difference between the treatment groups can be inferred from this.
  • With regard to specific adverse events, a statistically significant advantage of belimumab plus patient-specific concomitant medication over placebo plus patient-specific concomitant medication was observed for the endpoint ‘infections and parasitic diseases’ (System Organ Class (SOC)).
  • In the category of side effects, the overall analysis shows a statistically significant advantage of belimumab plus individualised concomitant medication compared with placebo plus individualised concomitant medication.
• Overall assessment / Conclusion
  • The PLUTO study provides findings on mortality, morbidity, quality of life and side effects. Usable results were presented only for the endpoints in the categories of mortality and side effects. The results for the endpoints in the morbidity category (severe relapses) cannot be conclusively assessed, and health-related quality of life cannot be interpreted due to the method of analysis employed by the pharmaceutical manufacturer.
  • No deaths occurred in the PLUTO study.
  • In the ‘side effects’ category, the overall analysis shows a statistically significant advantage of belimumab plus patient-specific concomitant medication compared with placebo plus patient-specific concomitant medication. The observed positive effect of belimumab in the ‘side effects’ category for the SUEs is not entirely called into question by the data on the endpoints in the ‘morbidity’ and ‘health-related quality of life’ categories, which cannot be conclusively assessed or interpreted. Due to the inability to conclusively evaluate the data on morbidity and the inability to interpret the data on health-related quality of life, the observed advantage of belimumab plus patient-specific concomitant medication compared with placebo plus patient-specific concomitant medication in the ‘side effects’ category is non-quantifiable.
  • Overall, belimumab as an add-on therapy for children and adolescents aged 5 to 17 years with active, autoantibody-positive systemic lupus erythematosus (SLE) who exhibit high disease activity despite standard therapy.

Courtesy translation only, please refer to the German original.