Among patients with paroxysmal nocturnal hemoglobinuria (PNH), inhibiting the terminal complement pathway may work synergistically with proximal complement inhibition, according to a review published in The New England Journal of Medicine. Given the high risk of financial toxicity of using both a C5 and a C3 inhibitor, however, a combination bargain deal may be necessary, should this therapeutic strategy prove revolutionary with further research.

PNH is an acquired hemolytic anemia characterized by intravascular hemolysis, thrombosis risk, and bone marrow impairment. Although it is rare, PNH is well-studied, in part because of its centrality among hemolytic anemias, thrombophilia, and the complement system, according to the authors of the present review.

Targeting of the complement system has previously been shown to be effective in managing PNH. Both eculizumab, a C5 inhibitor, and more recently, pegcetacoplan, a C3 inhibitor, have been shown to be efficacious in the PNH setting. There has not, however, been a close analysis of the varying effects and adverse events linked with the proximal vs terminal complement pathway.

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The authors noted, firstly, that although pegcetacoplan is linked with lactate dehydrogenase (LDH)-level increases of up to 15 times past normal levels, which is linked with a discontinuation rate of 15% at 48 weeks, LDH increases in eculizumab of up to 5 times past normal levels are rare.

Breakthrough hemolysis occurrence varies, depending partially on the incompleteness of proximal pathway inhibition. The authors noted that the risk of breakthrough hemolysis is likely to depend on which component is targeted, the mechanism of inhibition, and patient characteristics.

Dual complement inhibition is suggested, lastly, to prevent breakthrough hemolysis — which the authors noted is a life-threatening issue in the PNH setting.

“The combined approach might prevent C3 binding to PNH red cells and thus extravascular hemolysis, in addition to preventing massive breakthrough hemolysis,” the authors wrote. “Thus, such an approach would improve clinical benefits with respect to both efficacy and safety in controlling hemolysis in patients with PNH.”

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 


Notaro R, Luzzatto L. Breakthrough hemolysis in PNH with proximal or terminal complement inhibition. N Engl J Med. 2022;387(2):160-166. doi:10.1056/NEJMra2201664