In patients with paroxysmal nocturnal hemoglobinuria (PNH), treatment with crovalimab is well tolerated and is associated with sustained terminal inhibition, according to findings from the phase 1/2 COMPOSER trial published in the European Journal of Haematology.

Treatment with terminal complement inhibitors that target C5, including eculizumab and ravulizumab, is the current standard of care for individuals with PNH.  Although long-term clinical benefits, such as improved overall survival, enhanced quality of life, and control of hemolysis and transfusion requirements, have been linked to use of these agents, unmet medical needs remain. In fact, some patients receiving currently available C5 inhibitors experience residual intravascular hemolysis and breakthrough hemolysis and the ongoing need for transfusions.

The novel anti-C5 monoclonal antibody crovalimab exhibits pH-dependent, target-binding enhanced recycling by the neonatal Fc receptor and high subcutaneous bioavailability. These features permit small-volume subcutaneous administration once every 4 weeks, as opposed to the intravenous route of administration required with eculizumab and ravulizumab.

The investigators sought to explore the long-term outcomes from the open-label extension (OLE) of the COMPOSER trial in which crovalimab therapy was evaluated in treatment-naive individuals with PNH or those with the disorder who were switched from eculizumab at enrollment.

Read more about experimental therapies for patients with PNH

In COMPOSER, patients were enrolled at 14 sites in 6 countries (France, Germany, Hungary, Italy, Japan, and Korea). Individuals with PNH and healthy volunteers comprised the study population. The analysis was divided into 4 sequential parts, followed by the OLE:

  • Part 1: single ascending dose in healthy volunteers.
  • Part 2: intrapatient dose escalation in treatment-naive patients with PNH.
  • Part 3: dose-regimen and regimen finding in patients who switched from eculizumab to crovalimab.
  • Part 4: evaluation of optimized dosing regimen that was developed with the use of dose-optimization simulations based on data from parts 1 through 3 in both C5 inhibitor-naive patients and patients who switched from eculizumab to crovalimab.

Patients from Parts 2, 3, or 4 could then enter the OLE period.

The primary OLE objective of COMPOSER was evaluation of the long-term safety of crovalimab. The secondary study objective was assessment of the pharmacokinetics/pharmacodynamics of crovalimab. The exploratory endpoints included change in lactate dehydrogenase levels, avoidance of transfusion, hemoglobin stabilization, and breakthrough hemolysis.

Overall, 43 of 44 patients who underwent the primary treatment entered the OLE. Among these individuals, 32% (14 of 44) experienced treatment-related adverse events, with 77% of these events being mild or moderate in severity. Pharmacokinetic/pharmacodynamic analysis showed that over long-term follow-up, crovalimab concentrations of more than 100 μg/mL were associated with inhibition of the terminal complement activity.

Mean normalized lactate dehydrogenase was maintained at 1.5 times the upper limit of normal or less. Transfusion avoidance was attained in 83% to 92% of participants; hemoglobin stabilization was achieved in 79% to 88% of patients across 24-week intervals. Five breakthrough hemolysis events occurred, with no discontinuation needed.

“Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved,” the researchers noted. “Intravascular hemolysis control, hemoglobin stabilization, and transfusion avoidance were maintained, signifying long-term crovalimab efficacy,” they concluded.


Röth A, Ichikawa S, Ito Y, et al. Crovalimab treatment in patients with paroxysmal nocturnal haemoglobinuria: long-term results from the phase I/II COMPOSER trial. Eur J Haematol. 2023;111(2):300-310. doi:10.1111/ejh.14011