Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT

Abstract

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.

Keywords: complement inhibition; compstatin; eculizumab; extravascular hemolysis; intravascular hemolysis; paroxysmal nocturnal hemoglobinuria; ravulizumab.

Figure 1

Complement activation on PNH erythrocytes. (A) PNH erythrocytes inabsence of anti-complement treatment. The complement system may activate due to different triggers through the alternative, classical and mannose/lectin pathway. Spontaneous C3 tick-over continuously generates low-grade activation of the alternative pathway in the fluid phase and possible binding of activated C3 fragments on erythrocytes. Due to the lack of CD55, this leads on PNH erythrocytes to the generation of C3 convertase, with further generation of C3b, which eventually leads to the assembly of C5 convertase. Then, the terminal pathway of the complement cascade is activated, with the generation of the MAC, eventually leading to lysis of PNH erythrocytes lacking CD59. (B) PNH erythrocytes on terminal complement inhibitors. Terminal complement inhibitors (i.e., anti-C5 agents) prevent the cleavage of C5 into C5a and C5b, thereby disabling the formation of the MAC. Thus, PNH erythrocytes are largely protected from intravascular lysis. Nevertheless, early phases of surface complement activation remain uncontrolled on PNH erythrocytes due to the lack of CD55; thus, continuous low-grade activation continues leads to opsonization of PNH erythrocytes with C3 fragments. This excess of C3 generates high-affinity C5 convertases, which may account for residual intravascular hemolysis due to pharmacodynamic breakthrough (in addition to possible pharmacokinetic breakthrough due to sub-therapeutic plasma leven of anti-C5 agent). Moreover, C3 opsonization leads to extravascular hemolysis due to C3-specific receptors expressed on professional macrophages in the liver and in the spleen. (C) PNH erythrocytes on proximal complement inhibitors(± terminal complement inhibitors). Proximal complement inhibitors intercept complement activation at the level of its key component C3 (i.e., anti-C3 agents), or even upstream at the level of initial activation of the alternative pathway (i.e., anti-FD and anti-FB agents). All these agents prevent early activation of complement on the surface of PNH erythrocytes, counterbalancing the deficiency of the complement regulators CD55 and CD59. Based on theoretical assumptions and in vitro data, proximal complement inhibitors prevent C3 opsonization, thereby preventing C3-mediated extravascular hemolysis. However, by disabling early surface complement activation, proximal complement inhibitors should also prevent intravascular hemolysis. While preliminary clinical data already confirmed that proximal complement inhibitors prevent C3-mediated extravascular hemolysis, ongoing investigation will make clear whether they can adequately prevent intravascular hemolysis even in the absence of terminal inhibitors (as already documented in vitro).