Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial

Risitano, Antonio M.; Röth, Alexander; Soret, Juliette; Frieri, Camilla; Fontbrune, Flore Sicre de; Marano, Luana; Alashkar, Ferras; Benajiba, Lina; Marotta, Serena; Rozenberg, Izabela; Milojevic, Julie; End, Peter; Nidamarthy, Prasanna Kumar; Junge, G.; Latour, Régis Peffault de

doi:10.1016/s2352-3026(21)00028-4

Cited by 76 publications

(73 citation statements)

References 28 publications

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“…As an alternative to C5 inhibition with Eculizumab, several AP-targeted therapeutics, including the fD inhibitor Danicopan (ACH-4471) (46) and the fB inhibitor Iptacopan (LNP023) (38) are currently being evaluated in the clinic, and successful phase 2 clinical trials with both agents against PNH have been recently reported (47,48). However, reports that fB and fD deficient individuals are known to present with recurring invasive pneumococcal and meningococcal disease, underscores the importance of the AP in immunity against these bacteria (19,20).…”

Section: Discussionmentioning

confidence: 99%

Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals

et al. 2021

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Dysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors.

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Section: Discussionmentioning

confidence: 99%

Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals

et al. 2021

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“…Several orally administered complement inhibitors have also been developed. Vemricopan and danicopan inhibit FD in the AP (193), while iptacopan targets FB (194). In addition, avacopan, a selective C5aR inhibitor, has been approved for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and has been tested in patients with aHUS (195).…”

Section: Targeting Complement Activation In Kidney Transplant Recipientsmentioning

confidence: 99%

Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application

Qin

2022

Front. Immunol.

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Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia–reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.

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“…These data demonstrated that in poor responders to eculizumab, iptacopan, at a chronic dose of 200 mg twice a day, was able to better control intravascular haemolysis and to prevent C3-mediated extra-vascular haemolysis, leading to remarkable improvement of haemoglobin levels, even in monotherapy. 93 Additional data on the use of iptacopan in monotherapy come from an ongoing phase II study enrolling treatmentnaive PNH patients. Preliminary data from 13 patients who have been randomized to different doses of iptacopan (25 mg, followed by 100 mg twice a day or 50 mg followed by 200 mg twice a day) demonstrated control of intravascular haemolysis in all treated patients.…”

Section: New Proximal Complement Inhibitorsmentioning

confidence: 99%

How we(’ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future

Risitano

Latour

2021

Br J Haematol

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Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by complement-mediated intravascular haemolysis, severe thrombophilia and bone marrow failure. While for patients with bone marrow failure the treatment follows that of immune-mediated aplastic anaemia, that of classic, haemolytic PNH is based on anti-complement medication. The anti-C5 monoclonal antibody eculizumab has revolutionized treatment, resulting in control of intravascular haemolysis and thromboembolic risk, with improved long-term survival. Novel strategies of complement inhibition are emerging. New anti-C5 agents reproduce the safety and efficacy of eculizumab, with improved patient convenience. Proximal complement inhibitors have been developed to address C3-mediated extra-vascular haemolysis and seem to improve haematological response.

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Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial

Cited by 76 publications

References 28 publications

Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals

Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals

Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application

How we(’ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future

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