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

Q1 · MEDICINE

Article

Author: Nichols, Laura L ; Drage, Martin ; Horsfield, Catherine ; Kassimatis, Theodoros ; Rebollo-Mesa, Irene ; Olsburgh, Jonathon ; Qasem, Anass ; Douiri, Abdel ; Greenlaw, Roseanna ; Hunter, James P ; Friend, Peter J ; Flach, Clare ; Smith, Richard A ; Neri, Flavia ; Sacks, Steven H ; Karegli, Julieta ; Danzi, Guilherme

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.

01 Dec 2017·TrialsQ4 · MEDICINE

A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial

Q4 · MEDICINE

ArticleOA

Author: Olsburgh, Jonathon ; Qasem, Anass ; Smith, Richard A ; Nichols, Laura L ; Sacks, Steven H ; Douiri, Abdel ; Kassimatis, Theodoros ; Rebollo-Mesa, Irene ; Greenlaw, Roseanna ; Drage, Martin ; Ryan, Elizabeth G

BACKGROUNDDelayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation.METHODS/DESIGNEMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5-25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events.DISCUSSIONThe EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique 'cytotopic' property that permits its retention in the organ microvasculature.TRIAL REGISTRATIONISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.

01 Feb 2016·British Journal of PharmacologyQ2 · MEDICINE

APT070 (mirococept), a membrane‐localizing C3 convertase inhibitor, attenuates early human islet allograft damage in vitro and in vivo in a humanized mouse model

Q2 · MEDICINE

Article

Author: Ma, Liang ; Pingitore, Attilio ; Jones, Peter M ; Huang, Guocai ; Xiao, Fang ; Smith, Richard A ; Persaud, Shanta ; Lechler, Robert ; Dorling, Anthony ; Lombardi, Giovanna ; Zhao, Min

Background and PurposeA major obstacle to islet cell transplantation is the early loss of transplanted islets resulting from the instant blood‐mediated inflammation reaction (IBMIR). The activation of complement pathways plays a central role in IBMIR. The aim of this study was to test the inhibitory effect of “painting” human islets with APT070, a membrane‐localizing C3 convertase inhibitor, on inflammation evoked by exposure to human serum in vitro and by transplantation in vivo in a humanized diabetic mouse model.Experimental ApproachIn vitro, human islets pre‐incubated with APT070 were exposed to allogeneic whole blood. In vivo, similarly treated islets were transplanted underneath the kidney capsule of streptozotocin‐induced diabetic NOD‐SCID IL2rγ−/− mice that had been reconstituted with human CD34+ stem cells. Complement activation and islet hormone content were assayed using enzyme‐linked immunosorbent assays. Supernatants and sera were assayed for cytokines using cytometric beads array. Morphology of the islets incubated with human serum in vitro and in graft‐bearing kidney were evaluated using immunofluorescence staining.Key ResultsPre‐incubation with APT070 decreased C‐peptide release and iC3b production in vitro, with diminished deposition of C4d and C5b‐9 in islets embedded in blood clots. In vivo, the APT070‐treated islets maintained intact structure and showed less infiltration of inflammatory cells than untreated islets. The pretreatments also significantly reduced pro‐inflammatory cytokines in supernatants and sera.Conclusions and ImplicationsPre‐treatment of islets with APT070 could reduce intra‐islet inflammation with accompanying preservation of insulin secretion by beta cells. APT070 could be as a potential therapeutic tool in islet transplantation.

100 Deals associated with Mirococept

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Reperfusion Injury	Phase 3	-	Adprotech Ltd.	-
Myocardial Reperfusion Injury	Phase 3	-	Inflazyme Pharmaceuticals	-
Inflammatory Bowel Diseases	Phase 1	GB	Inflazyme Pharmaceuticals	-
Graft Rejection	Preclinical	GB	Inflazyme Pharmaceuticals	-
Inflammation	Preclinical	GB	Inflazyme Pharmaceuticals	-
Reperfusion Injury	Preclinical	GB	Adprotech Ltd.	-
Rheumatoid Arthritis	Preclinical	GB	Inflazyme Pharmaceuticals	-
Shock	Preclinical	CA	Inflazyme Pharmaceuticals	-

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