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Ex vivo delivery of Mirococept: A dose‐finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney
Author(s) -
Kassimatis Theodoros,
Greenlaw Roseanna,
Hunter James P.,
Douiri Abdel,
Flach Clare,
RebolloMesa Irene,
Nichols Laura L.,
Qasem Anass,
Danzi Guilherme,
Olsburgh Jonathon,
Drage Martin,
Friend Peter J.,
Neri Flavia,
Karegli Julieta,
Horsfield Catherine,
Smith Richard A.,
Sacks Steven H.
Publication year - 2021
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.16265
Subject(s) - medicine , ex vivo , kidney , kidney transplantation , transplantation , in vivo , urology , renal function , pharmacology , ischemia , surgery , biology , microbiology and biotechnology
The complement system plays a pivotal role in the pathogenesis of ischemia–reperfusion injury in solid organ transplantation. Mirococept is a potent membrane‐localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia‐reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5‐25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.