Konstantin Doberer1, Michael Duerr2, Philip F Halloran3, Farsad Eskandary1, Klemens Budde2, Heinz Regele4, Jeff Reeve3, Anita Borski1, Nicolas Kozakowski4, Roman Reindl-Schwaighofer1, Johannes Waiser2, Nils Lachmann5, Sabine Schranz6, Christa Firbas6, Jakob Mühlbacher7, Georg Gelbenegger6, Thomas Perkmann8, Markus Wahrmann1, Alexander Kainz1, Robin Ristl9, Fabian Halleck2, Gregor Bond1, Edward Chong10, Bernd Jilma11, Georg A Böhmig12. 1. Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria. 2. Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany. 3. Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada. 4. Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria. 5. Centre for Tumor Medicine, Histocompatibility & Immunogenetics Laboratory, Charité Universitätsmedizin Berlin, Berlin, Germany. 6. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 7. Department of Surgery, Medical University of Vienna, Vienna, Austria. 8. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. 9. Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria. 10. Vitaeris Inc., Vancouver, Canada. 11. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria georg.boehmig@meduniwien.ac.at bernd.jilma@meduniwien.ac.at. 12. Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria georg.boehmig@meduniwien.ac.at bernd.jilma@meduniwien.ac.at.
Abstract
BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.
BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.
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