Use of the complement inhibitor Coversin to treat HSCT-associated TMA

Goodship, Timothy H.J.; Pinto, Fernando; Weston-Davies, Wynn H.; Silva, Juliana; Nishimura, Junichi; Nunn, Miles A.; Mackie, Ian; Machin, Samuel J.; Palm, Liina; Pryce, Jeremy; Chiesa, Robert; Amrolia, Persis; Veys, Paul

doi:10.1182/bloodadvances.2016002832

Cited by 39 publications

(30 citation statements)

References 22 publications

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“…The efficacy of Coversin in suppressing inflammation in C5-driven conditions has previously been reported for thrombotic microangiopathy, polymicrobial sepsis, antiphospholipid syndrome, myasthenia gravis, and myocardial infarction, among others (19)(20)(21)(22)(23)(24)(25). In contrast, the effect of Coversin on conditions driven by LTB 4 has been investigated only in an acute, 4-hour-long mouse model of immune complex-induced lung injury, where the inhibition of both C5 and LTB 4 by Coversin contributed to the therapeutic effect (15).…”

Section: Discussionmentioning

confidence: 80%

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

et al. 2019

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Section: Discussionmentioning

confidence: 80%

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

et al. 2019

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“…A rare polymorphism in C5 (p.R885H) has been reported in the Japanese population which prevented eculizumab binding [ 52 ]. More recently, a European with a functionally significant CFH mutation (p.D1119G) and a TMA post-bone marrow transplant was shown to carry this SNP preventing the use of eculizumab [ 53 ]. In this case, an alternative C5 inhibitor, Coversin, was used.…”

Section: Pathologymentioning

confidence: 99%

“…This is a recombinant protein derived from the tick, Ornithodoros moubata . As this binds to a different epitope on C5, this completely blocked the terminal pathway and there appeared to be a clinical response although there was a limited supply of the drug and the patient died [ 53 ].…”

Section: Pathologymentioning

confidence: 99%

Diseases of complement dysregulation—an overview

Wong

Kavanagh

2018

Semin Immunopathol

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Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease. Eculizumab has revolutionized the treatment of PNH and aHUS although has been less successful in C3G. With the next generation of complement therapeutic in late stage development, these archetypal complement diseases will provide the initial targets.

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“…81 LFG316, a fully human monoclonal antibody against C5, is in phase 2 clinical trial in patients with TA-TMA (Clinical trial ID NCT02763644). In a recently published case report, 82 Coversin (rEV576), a recombinant protein derived from the saliva of Ornithodros moubata tick and acts as C5 inhibitor, is found to be beneficial in TA-TMA resistant to eculizumab. CCX168 is an oral C5a receptor antagonist in a phase 2 clinical trial in patients with aHUS (Clinical trial ID NCT02464891) and holds promise as a potential replacement for corticosteroids due to blockade of inflammation caused by C5a.…”

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confidence: 99%

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

Khosla

Yeh

Spitzer

et al. 2017

Bone Marrow Transplant

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Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) remains a difficult complication to address due to its high mortality rate, lack of standard diagnostic criteria and limited therapeutic options. Underscoring this challenge is the complex pathophysiology involved and multiple contributing factors that converge on a final pathway involving widespread endothelial injury and complement activation. In addressing our current understanding of TA-TMA, we highlight the risk factors leading to endothelial damage and a pathophysiological cascade that ensues. We have also compared the different definition criteria and biomarkers that can enable early intervention in TA-TMA patients. Current first-line management includes discontinuation or alteration of the immunosuppressive regimen, treatment of co-existing infectious and GVHD, aggressive hypertension control and supportive therapy. We discuss current pharmacological therapies, including newer agents that target the complement cascade and nitric oxide pathways.

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Use of the complement inhibitor Coversin to treat HSCT-associated TMA

Abstract: Key points Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor. Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab.

Cited by 39 publications

References 22 publications

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

Diseases of complement dysregulation—an overview

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

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