Belimumab (1) – Benlysta®

a) adult patients with active autoantibody-positive systemic lupus erythematosus (SLE) who, despite standard therapy, exhibit high disease activity (e.g. a positive test for anti-dsDNA antibodies and low complement) and who are receiving concomitant medication authorised in Germany

• The certainty of the finding (probability of additional benefit) is classified in the ‘indication’ category.
• The G-BA classifies the extent of the additional benefit of belimumab as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a significant improvement in treatment-related benefit not previously achieved, as it results in a reduction in serious symptoms or alleviation of the disease.
• Morbidity – SLE Responder Index (SRI)
  • In the registration trials BLISS-52 and BLISS-76, as well as in the Phase II trial LBSL02, the SLE Responder Index (SRI) was selected as the primary endpoint.
  • The G-BA considers this composite endpoint to be clinically relevant.
  • The effect size for belimumab (10 mg/kg body weight) in the meta-analysis of the BLISS-52 and BLISS-76 studies is (OR = 2.365, CI [1.559–3.589]; ARR = 17.2%).
  • Both studies also achieved statistical significance for belimumab at the primary endpoint when analysed individually. However, the data from BLISS-76 (OR = 2.07 [CI 1.05–4.09]; ARR = 13.3%) showed a minor effect compared to BLISS-52 (OR = 2.56 [CI 1.52–4.09]; ARR = 19.5%).
  • The results from the LBSL02 study for the patient group ‘adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who, despite standard therapy, exhibit high disease activity (e.g. positive test for anti-dsDNA antibodies and low complement levels)”, were not statistically significant with regard to the primary endpoint.
  • The effects of the individual components (SELENA-SLEDAI score, BILAG index; PGA) of the SRI were recorded as secondary endpoints in the studies and are regarded as supplementary information to the primary endpoint. The meta-analytical evaluation shows significant differences in each of the individual components.
  • It should be noted that, for the BILAG index and PGA endpoints in the BLISS-76 study, there was no statistical significance for the patient group considered by the G-BA.
• Morbidity – flares (prevention of severe flares according to the SELENA-SLEDAI Flare Index (SFI))
  • The G-BA considers the prevention of flares in the treatment of SLE to be relevant to patients.
  • With regard to the endpoint ‘flare-ups (SLE Flare Index, SFI)’, the operationalisation of the endpoint and the categorisation of severity levels are not sufficiently explained by the pharmaceutical manufacturer in the dossier. To ensure patient relevance, the G-BA therefore only takes into account the prevention of severe flares as measured by the SFI.
  • For the endpoints ‘time to first severe flare’ and ‘number of severe flares per patient-year’, there is a positive and significant effect for belimumab.
  • For the endpoint ‘time to first relapse (1A/2B)’, there is no significant difference for belimumab. For the endpoint ‘number of relapses per patient-year’, there is a positive, significant effect for belimumab.
• Morbidity – Fatigue
  • Disease-related fatigue is regarded as a relevant symptom of SLE.
  • The pharmaceutical manufacturer did not provide details of the validation of the assessment tool in the dossier.
  • The G-BA notes that no usable data are available for the symptom of fatigue.
• Morbidity – Reduction in glucocorticoid dosage
  • Reducing the glucocorticoid dosage in the treatment of SLE is a recognised therapeutic goal.
  • The endpoints presented by the pharmaceutical manufacturer in the dossier – “reduction by ≥25% to ≤ 7.5 mg prednisolone dose equivalent per day”, ‘reduction to ≤ 7.5 mg prednisolone dose equivalent per day by week 52’, “increase to > 7.5 mg prednisolone equivalent per day by week 52” show no significant differences in the meta-analytic summary of the BLISS studies.
• Health-related quality of life
  • These endpoints did not show any statistical significance in the results.
• Side effects
  • In the registration trials, there were no significant differences between the control group and the belimumab group with regard to the incidence of side effects.
  • However, in March 2012, a warning was issued via a ‘red-hand’ letter, stating that the use of Benlysta® may lead to severe or life-threatening hypersensitivity and infusion reactions.
• Overall assessment
  • In its overall assessment of all endpoints, the G-BA quantifies the extent of the additional benefit as ‘considerable’.
  • The decisive factors here are the results for the primary endpoint, SRI, and the prevention of relapses. This represents more than just a moderate improvement in treatment-related benefit.

Courtesy translation only, please refer to the German original.