Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial.
Flint, Shaun M
Shanahan, Don N
Chadwick, Joseph A
Foster, Katie E
Savage, Caroline O
Henderson, Robert B
Lancet (London, England)
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Banham, G. D., Flint, S. M., Torpey, N., Lyons, P., Shanahan, D. N., Gibson, A., Watson, C., et al. (2018). Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial.. Lancet (London, England), 391 (10140), 2619-2630. https://doi.org/10.1016/s0140-6736(18)30984-x
Background: B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. In contrast, regulatory B cells are associated with transplant tolerance. There is an unmet need for immunotherapies that inhibit B cell effector function, including antibody secretion, whilst sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B cell activation, and has not previously been targeted in kidney transplant recipients. Aim: We sought to examine the safety and activity (the latter measured by a reduction in naïve B cells from baseline to week 24) of an anti-BLyS antibody, belimumab, in addition to standard of care immunosuppression in adult kidney transplant recipients. We utilised an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de novo IgG and on the regulatory B cell compartment. Methods: We conducted a phase 2 double-blind randomised placebo-controlled trial of belimumab, in addition to standard of care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus and prednisolone), in adults aged 18-75 receiving a kidney transplant. Subjects were randomised at a single centre, Addenbrooke’s Hospital (UK), stratified according to receipt of a living or deceased donor organ. Within each stratum subjects were randomised by telephone in a 1:1 ratio to receive intravenous belimumab 10mg/kg or placebo (day 0, 14, 28 and every four weeks thereafter for a total of seven infusions). Coprimary endpoints were safety and change in naïve B cells from baseline to Week 24. This trial has completed and is registered as ClinicalTrials.gov number NCT01536379 and EudraCT number 2011-006215-56. Findings: 28 kidney transplant recipients were randomised to belimumab (n=14) or placebo (n=14) treatment between 13th September 2013 and 8th February 2015. Twelve belimumab and 13 placebo patients were transplanted and went on to receive at least one dose of 3 belimumab/placebo (modified intention to treat (MITT) population). We observed similar rates of adverse events in belimumab and placebo groups, including serious infection (1/12 (8%) and 5/13 (38%) respectively during the six month on-treatment phase; 0/13 (0%) and 2/13 (15%) during the six month post-treatment follow-up phase). There was one death in the ontreatment phase in a patient in the placebo group. The co-primary endpoint of a reduction in naïve B cells from baseline to week 24 was not met; treatment with belimumab resulted in a trend towards, but not a statistically significant reduction in naïve B cells from baseline to week 24 (adjusted mean difference -34·4 cells/mm3 (95% confidence interval (CI) -109·5 to 40·7)). Interpretation: Treatment with belimumab in addition to standard of care immunosuppression in low immunological risk renal transplant recipients was not associated with an adverse safety signal nor an increased risk of infection.
Humans, Immunoglobulin G, Immunosuppressive Agents, Immunosuppression, Kidney Transplantation, Double-Blind Method, Graft Survival, Adult, Aged, Middle Aged, Female, Male, Antibodies, Monoclonal, Humanized, Administration, Intravenous
NIHR; Glaxo Smith Kline
External DOI: https://doi.org/10.1016/s0140-6736(18)30984-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279573