Clinical signs arising from intravascular hemolysis, hemolysis-related transfusions and thrombosis are indications for treatment initiation in paroxysmal nocturnal hemoglobinuria (PNH), whereas clone size per se is not. Eculizumab prevents intravascular hemolysis and reduces significantly thromboembolic risk resulting in a five-year overall survival of >90%. Hemoglobin value, LDH and reticulocyte count are used to define treatment response.
Residual intravascular hemolysis is mainly caused by an incomplete C5 blockage and can lead to continuous low‐grade hemolysis or transient breakthrough hemolysis episodes in 10-15% of PNH patients. Additional complement‐amplifying conditions such as infections, surgery or pregnancy may overcome efficient therapeutic levels of Eculizumab and therefore require dose adjustments.
C3‐mediated extra‐vascular hemolysis represents the main reason for residual anemia during anti‐C5 treatment. Patients with an inherited C5-variant lack response to Eculizumab and have been directed (in past) towards allogeneic HSCT. Transplantation has an overall mortality of up to 30%, with a higher risk in patients with previous thrombosis.
A plethora of novel therapeutic agents are reported to impact on both; residual intravascular hemolysis and C3‐mediated extra‐vascular hemolysis. The new C5 inhibitor Ravalizumab with an eight‐week i.v. dosing interval showed non-inferiority to Eculizumab. Crovalimab, binding on the single missense C5 heterozygous mutation is injected s.c. monthly; two large phase III trials are ongoing as add on- and mono-therapy. Others, such as Pozelimab, injected subcutaneously on a weekly basis after an initial IV loading dose or Tesidolumab are still under current investigation.
Currently investigated proximal inhibitors are acting towards: (i) the C3 complement; (ii) complement factor D or (iii) the complement factor B. They are aiming in particular to prevent C3‐mediated extra‐vascular hemolysis. Pegcetacoplan is a PEGylated version of compstatin which binds to C3 and is injected s.c. in monotherapy 4 weeks after initial concomitant therapy with Eculizumab. In a recent phase III trial, pegcetacoplan showed superiority to eculizumab in hemoglobin change from baseline and is now approved by the FDA for patients with PNH who are either treatment‐naive or switching from anti‐C5 monoclonal antibodies. Danicopan is an oral first‐in‐class factor D complement alternative pathway inhibitor and decreased significantly transfusion requirement, as shown in a phase II trial (phase III ongoing). BCX9930, another FD inhibitor in early development is given orally and demonstrated initial clinical efficacy both as add‐on therapy in patients with inadequate response to eculizumab as well as in monotherapy in treatment‐naive patients.
In conclusion, novel proximal and distal complement inhibitors with different application modalities, in part as add-on or monotherapy seem to improve significantly intra- and extra‐vascular hemolysis in PNH, resulting in a better hematological benefit. Before choosing specific treatment, hematologists have to assess hemolysis, thrombosis and patients‘ bone marrow function. Future studies will help to explore long-term efficacy and safety of these novel agents.
