A randomised biomarker enrichment trial: IgA2 anti-DNA antibodies as a biomarker of response to belimumab after rituximab in systemic lupus erythematosus - STRATIFY lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by diverse patterns of organ involvement and wide variations in response to treatment. SLE is one of the top ten causes of death in young women with the worst outcomes in ethnic minorities. Because of high cost and only modest effectiveness, access to novel licensed therapies for SLE is highly restricted in England and reliance on treatment with corticosteroids remains. Tailoring (targeting) treatments to those patients most likely to respond could be considered the holy grail of lupus therapy but has yet to be achieved. We have reported encouraging results from the BEAT-Lupus clinical trial, funded by VersusArthritis, which tested the effectiveness of two ‘targeted’ therapies, belimumab and rituximab, used in combination for refractory disease. Rituximab depletes B cells and belimumab binds to a molecule (BAFF) that activates B cells (B cells produce autoantibodies that cause harm in SLE). The BEAT-Lupus trial demonstrated that patients treated with belimumab after rituximab had fewer severe disease flares compared to patients who received rituximab alone. But there was only a modest non-significant difference (13%) in the proportion of patients that responded at 1 year between the combination treatment and rituximab alone. Using machine learning (a form of artificial intelligence) applied to data from blood samples taken during the BEAT-lupus trial, we identified IgA2 anti-DNA antibody levels in blood as a predictor of response (biomarker) to belimumab after rituximab in the BEAT-lupus trial. We validated (confirmed) this predictive biomarker using samples from another trial conducted in the US testing the same combination belimumab after rituximab in refractory lupus nephritis, the CALIBRATE trial. Combining data from both trials, the difference in the proportion of responding patients between belimumab and rituximab combination compared to rituximab increased from 14% overall to 59% in patients with high levels of IgA2 anti-dsDNA antibodies. In this proposal, we plan a biomarker enrichment placebo-controlled double blind clinical trial (STRATIFY lupus), where corticosteroid and immune suppressant dose will be limited, to prospectively test the value of serum IgA2 anti-dsDNA antibodies as a predictive biomarker potentially taking the guesswork out of when to use this combination therapy for lupus patients. In patients with high serum levels of this biomarker, we hypothesise that belimumab after rituximab will lead to many more patients responding compared to rituximab alone. This multicentre trial will randomise 66 lupus patients with high serum IgA2 anti-DNA antibodies who are refractory to conventional therapy to receive combination belimumab after rituximab or placebo after rituximab, and have a clinical primary endpoint after 12 months of therapy with secondary endpoints to include achievement of remission. A positive trial will help to ensure access to this treatment combination to those patients with SLE most likely to respond, whilst not using rituximab alone without belimumab in patients who would have a poor response. Sample collection will facilitate continuation of the experimental medicine approach which began with understanding the effects of rituximab alone and has led to the design of this first-in-lupus landmark biomarker enrichment trial.