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.

The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria

“…The broad inclusion criteria of part 3, allowing patients with recent transfusion, elevated LDH, recent history of BTH, or higher-than-label dose eculizumab, resulted in an enrichment of patients in the study population who had a relatively high body weight, needed more transfusions, and, in some cases, were on escalated doses of eculizumab. This population is likely to better reflect the general PNH population on C5 inhibitor treatment 17,18 and contrasts with the population of registration trials for ravulizumab that focused on well-controlled patients with relatively low average body weight. 2 Specifically, 11 of 19 patients in part 3 were on higher-than-label eculizumab dose, had LDH .1.53 ULN on eculizumab, and/or had residual clinically relevant complement activation at the trough of eculizumab, as indicated by LIA .10 U/mL.…”

PNH phenotypes and their genesis

“…As mentioned above, it is more than gratifying that since 2007 we have had eculizumab, as well as its now long‐acting derivative ravulizumab (Lee et al ., 2019). In addition, a number of small molecules are in the offing: from preliminary clinical data, proximal complement inhibitors hold real promise (Risitano et al ., 2019). As new therapeutic options become available, it is ever more relevant to chart the longterm course of PNH, from its onset in the context of AA – whether recognised or not – to full‐blown PNH, and subsequently.…”

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry

“…At the advent of eculizumab nearly two decades ago, efficacy measures of PNH treatment centered around transfusion independence and reductions in intravascular hemolysis as reflected by LDH levels. Now, additional measures such as assessments of hemoglobin levels and possibility of extravascular hemolysis are also taken into consideration 19 …”

“…An additional consideration when evaluating transfusion needs among patients with PNH is the potential for extravascular hemolysis (as defined by Risitano et al 22 ) occurring 1,19,22 in some patients with PNH receiving eculizumab 22‐30 ; data from some small, single‐center studies suggest that up to 72% of eculizumab‐treated patients are direct antiglobulin test positive (DAT+) 23,26 . In the absence of breakthrough hemolysis, patients may have more subtle signs of persistent low‐level hemolysis, such as slightly elevated LDH levels, or abnormal bilirubin, reticulocyte, and/or hemoglobin levels 30,31 .…”