Endopeptidase cleavage of anti-glomerular basement membrane antibodies in vivo in severe kidney disease: an open-label phase 2a study

Uhlin, F.; Szpirt, W.; Kronbichler, A.; Bruchfeld, A.; Soveri, I.; Rostaing, L.; Daugas, E.; Lionet, A.; Kamar, N.; Rafat, C.; Myslivecek, M.; Tesar, V.; Fernstrom, A.; Kjellman, C.; Elfving, C.; McAdoo, S.; Molne, J.; Bajema, I.; Sonesson, E.; Segelmark, M.

doi:doi:10.1681/ASN.2021111460

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 treat-ment 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 1.73m(2). 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 1.73m(2). The median age was 61 years (range 19-77), six were women, and six were also...Show moreBackground: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 treat-ment 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 1.73m(2). 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 1.73m(2). 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.Show less

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Endopeptidase cleavage of anti-glomerular basement membrane antibodies in vivo in severe kidney disease: an open-label phase 2a study