Belimumab in kidney transplantation – Authors' reply

We thank Ekaterini Christina Tampaki and colleagues for their interest in our study1Banham GD Flint SM Torpey N et al.Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial.Lancet. 2018; 391: 2619-2630Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar and in potential interracial differences in the response to belimumab in renal transplant recipients. As shown in Table 1,1Banham GD Flint SM Torpey N et al.Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial.Lancet. 2018; 391: 2619-2630Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar each treatment group had only one non-white participant. Subgroup analysis of outcomes between white and non-white participants was therefore neither appropriate nor feasible. We agree that long-term follow-up data are important. We reported rigorous follow-up data on adverse events (including infection, cancer, and suicide or self-harm events) for 1-year post-transplant and 6 months after cessation of belimumab. These data represent a reasonable follow-up period for a phase 2 study in this field and showed no safety issues. As with any patient on long-term immunosuppression, these renal transplant recipients will continue to have regular, careful, long-term follow-up of outcomes by their local clinicians. Notably, this phase 2 study was not designed to investigate long-term outcomes, but rather to provide proof of potential efficacy and the exclusion of a major early safety signal. Further studies using a larger cohort will be required to provide long-term efficacy and safety data in kidney transplant recipients. With regards to the use of the mixed model for repeated measures, this approach has been used in many clinical trials2Dungan KM Povedano ST Forst T et al.Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial.Lancet. 2014; 384: 1349-1357Summary Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 3Kanes S Colquhoun H Gunduz-Bruce H et al.Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.Lancet. 2017; 390: 480-489Summary Full Text Full Text PDF PubMed Scopus (228) Google Scholar and was one of the standard analysis strategies available when our study protocol was written. However, we acknowledge that the mixed model for repeated measures has been superseded by the use of multiple imputation techniques. To mitigate the effect of missing data in our study, sensitivity analyses were performed on the primary efficacy data, (eg, per-protocol analysis and non-parametric analysis). Our main conclusions are based on these per-protocol population analyses, including those examining peripheral blood transcriptomics, protein array estimation of IgG, and regulatory B-cell counts. We thank Sakir Ahmed for highlighting the challenges of selecting endpoints that accurately reflect the biological activity of interventions. We chose a reduction in naive B cells as a primary endpoint because of the known importance of B-lymphocyte simulator (BLyS) for naive B-cell survival,4Schiemann B Gommerman JL Vora K et al.An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway.Science. 2001; 293: 2111-2114Crossref PubMed Scopus (901) Google Scholar evidenced by their depletion in previous studies utilising belimumab.5Stohl W Hiepe F Latinis KM et al.Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus.Arthritis Rheum. 2012; 64: 2328-2337Crossref PubMed Scopus (274) Google Scholar When estimating the potential reduction in naive B cells that we might observe in the placebo group, we were aware that renal transplant recipients differ from previous cohorts who have received belimumab, in that they have end-stage renal failure (which is immunosuppressive) and receive substantial additional immunosuppression (triple maintenance therapy with tacrolimus, mycophenolate mofetil, and prednisolone, and basiliximab at induction). This consideration led us to do an enabling study on a historical cohort of renal transplant patients receiving the same standard of care as the trial population, to model the predicted effect of belimumab (detailed on p 7 of the appendix1Banham GD Flint SM Torpey N et al.Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial.Lancet. 2018; 391: 2619-2630Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar). However, the magnitude of the reduction in naive B cells in the control group was greater than in the enabling cohort, resulting in a failure to reach a significant difference between the placebo and belimumab groups. We agree that one simple measure cannot provide an accurate estimation of the effect of belimumab on the immune system; in fact, a strength of our study was the application of various mechanistic endpoints to more broadly investigate immune responses.6Geissler EK Hutchinson JA Immunological investigations empower transplant drug trials.Lancet. 2018; 391: 2578-2579Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar Furthermore, we agree that understanding the effect of belimumab on potentially tolerogenic regulatory B cells is of upmost importance. We were careful to assay interleukin (IL)-10-producing regulatory B cells in our study, showing that, in all compartments (including transitional B cells), belimumab was associated with an increase in the IL-10 to IL-6 ratio, suggesting a preservation, and even an enhancement, of this important subset. Overall, we did the most intensive interrogation of human immune responses after belimumab use to date, and our findings make a big step in moving our understanding of its action from ignorance to BLyS. GDB was funded by a Wellcome Trust Translational Medicine and Therapeutics PhD grant (102728/z/13/z). SMF received funding from GlaxoSmithKline for a GlaxoSmithKline Wellcome Trust Translational Medicine and Therapeutics PhD. SMF, DNS, and RBH are employees of and hold stock in GlaxoSmithKline. GDB and MRC have received grants from GlaxoSmithKline outside the submitted work. MRC is funded by a Medical Research Council New Investigator Research Grant (MR/N024907/1), and an Arthritis Research UK Cure Challenge Research Grant (21777) and receives support from the National Institute of Health Research Cambridge Biomedical Research Centre. RBH has a patent pending (number PB65956). Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trialBelimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity. Full-Text PDF Belimumab in kidney transplantationI read with interest the Article by Gemma D Banham and colleagues (June 30, 2018, p 2619).1 Inhibiting B-lymphocyte simulator (BLyS) has been an attractive target for immunomodulation. Belimumab is approved for use in systemic lupus erythematosus in the USA and in Europe, but it has indications restricted to non-life-threatening disease. About 5% of patients with lupus receive belimumab.2 In Banham and colleagues' phase 2 study1 of belimumab for recipients of kidney transplants, naive B-cell depletion from baseline to week 24 was a coprimary endpoint. Full-Text PDF Belimumab in kidney transplantationWe found it particularly interesting how belimumab leads to additional immunosuppression when used in combination with other immunosuppressive drugs.1 However, the use of belimumab as add-on therapy can complicate treatment because it moderately improved the response rate of belimumab in the study population on the basis of a complex endpoint showing uncertain clinical benefits without reducing corticosteroid requirements.1–3 Risk of infections (particularly opportunistic infections) and cancer is poorly documented. Full-Text PDF