It is caused by a deficiency in the red blood cell surface protein DAF that should inhibit the process. Symptoms include problems with breathing, concentration and exercise, tiredness and pains in the head, chest and stomach.
It can be treated with blood transfusions or the antibody C5 inhibitors eculizumab or ravulizumab. These block the last step of the complement cascade, reducing the rate at which red blood cells are destroyed.
However, they give incomplete inhibition. These antibodies must be given via infusion and an alternative C5 inhibitor, crovalimab, which can be administered in monthly subcutaneous doses is being developed by Roche.1
It also binds to C5 via a different site that may work for non-responders to existing therapies; it is also recycled into the circulation, which may overcome the issue of incomplete inhibition.
After showing promise in a single arm Phase III trial, a further open-label Phase III study was done to evaluate its non-inferiority.2,3
In this, 204 C5 inhibitor-naïve patients were given crovalimab or eculizumab for a primary treatment period of 24 weeks. It proved to be non-inferior in the coprimary endpoints of haemolysis control (79.3% compared with 79.0% for eculizumab) and 65.7% versus 68.1%, respectively, for transfusion avoidance.
Safety profiles were similar and most of those who switched to the new antibody after the primary treatment period preferred it. A Phase III trial has also been run comparing the antibody to eculizumab in C5 inhibitor-experienced PNH patients.4
In all, 89 subjects were given crovalimab or continued with eculizumab. The primary endpoint of efficacy had to be shifted to safety because target recruitment numbers were not achieved after the approval of the follow-up drug, ravulizumab, and all efficacy endpoints became exploratory.
During the primary treatment period of 24 weeks, 77% of crovalimab and 67% of eculizumab patients experienced adverse events, but none led to discontinuation or death.
About a sixth of the crovalimab group had transient immune complex reactions but most were mild or moderate and resolved without modifying treatment. Crovalimab gave sustained terminal complement activity inhibition and maintained disease control; 85% preferred the new treatment.
As well as PNH, it may have potential in other complement-mediated diseases. These include atypical haemolytic uraemic syndrome and sickle cell disease.
References
- A. Röth, et al., Blood 135, 912 (2020).
- H. Liu, et al., Am. J Hematol. 98, 1407 (2023).
- A. Röth, et al., Am. J. Hematol. (2024): online ahead of print (doi:10.1002/ajh.27412).
- P. Scheinberg, et al., Am. J Hematol. (2024): online ahead of print (doi:10.1002/ajh.27413).