Fredrik Uhlin1,2, Wladimir Szpirt3, Andreas Kronbichler4, Annette Bruchfeld1,5, Inga Soveri6, Lionel Rostaing7, Eric Daugas8, Arnaud Lionet9, Nassim Kamar10, Cédric Rafat11, Marek Mysliveček12, Vladimír Tesař12, Anders Fernström1, Christian Kjellman13, Charlotte Elfving13, Stephen McAdoo14, Johan Mölne15, Ingeborg Bajema16, Elisabeth Sonesson13, Mårten Segelmark17,18. 1. Department of Nephrology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden. 2. Department of Health Technologies, Tallinn University of Technology, Tallinn, Estonia. 3. Department of Nephrology P, Københavns universitet, Copenhagen, Denmark. 4. Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria. 5. Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden. 6. Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 7. Department of Nephrology, Hemodialysis, Apheresis, and Kidney Transplantation, EriCHU Grenoble-Alpes, Grenoble, France. 8. Nephrology Service, Hôpital Bichat, Université de Paris, Paris, France. 9. Neohrology service, Centre Hospitalier Regional, Lille University, Lille, France. 10. Department of Nephrology and Organ Transplantation, Université Paul Sabatier, Toulouse, France. 11. Urgences Néphrologiques et Transplantation Rénale, Paris, France. 12. Department of Nephrology, Charles University and General University Hospital, Prague, Czech Republic. 13. Hansa Biopharma, Lund, Sweden. 14. Department of Medicine, Imperial College London, London, United Kingdom. 15. Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden. 16. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. 17. Department of Nephrology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden Marten.segelmark@med.lu.se. 18. Department of Clinical Sciences, Lund University, Lund, Sweden.
Abstract
BACKGROUND: The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis. METHODS: An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR <15 ml/min per 1.73m2. All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months. RESULTS: At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m2. The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P<0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug. CONCLUSIONS: In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.Clinical Trial registration number: EUDRACT 2016-004082-39 https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001377-28/results.
BACKGROUND: The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis. METHODS: An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR <15 ml/min per 1.73m2. All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months. RESULTS: At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m2. The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P<0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug. CONCLUSIONS: In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.Clinical Trial registration number: EUDRACT 2016-004082-39 https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001377-28/results.
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