Complement biomarkers may not reliably track PNH disease activity
Standard blood test remains most informative for monitoring
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Blood markers designed to measure activation of the complement system, a part of the immune system involved in paroxysmal nocturnal hemoglobinuria (PNH), may not reliably reflect disease activity or red blood cell destruction in patients receiving complement-blocking therapies, a new study suggests.
The researchers found that although these complement biomarkers may help track complement inhibition, they did not reliably reflect disease activity. Lactate dehydrogenase (LDH), a marker of red blood cell destruction, remained the most informative test for monitoring patients on these treatments.
Study finds LDH remains key marker for monitoring PNH
“Our data suggest that in daily practice, LDH remains the most informative blood test in the monitoring of PNH patients on complement inhibitors,” the researchers wrote.
The study, “Complement Biomarkers for Monitoring Last-Generation Complement Inhibitors in Paroxysmal Nocturnal Hemoglobinuria Patients,” was published as correspondence in the American Journal of Hematology.
PNH is a rare blood disorder in which abnormal activation of the complement system leads to the destruction of red blood cells, a process called hemolysis, causing hallmark PNH symptoms.
Some PNH treatments, such as Soliris, work by blocking C5, a complement protein that acts near the end of the cascade. In doing so, they effectively prevent intravascular hemolysis, or red blood cell destruction occurring inside blood vessels, easing symptoms. However, they do not fully control extravascular hemolysis, which occurs outside blood vessels.
Newer therapies that act upstream, or before, C5 in the complement cascade have been developed. These include treatments such as Fabhalta (iptacopan), which targets factor B, and Voydeya (danicopan), which blocks factor D. By targeting earlier stages of complement activation, these therapies are thought to better control both forms of hemolysis.
“Despite our deeper biological understanding of target therapies in PNH,” data on biomarkers of complement activity in patients receiving these newer inhibitors “remain very limited,” the researchers noted.
To address this gap, researchers in Italy and the Netherlands analyzed 278 blood samples from 10 people with PNH treated at their center with complement inhibitors.
Researchers analyze patients treated with complement inhibitors
Two patients enrolled in a Phase 2 study (NCT03053102) evaluating Voydeya in PNH were tested before treatment and again while receiving the therapy. The remaining eight participated in a Phase 2 trial (NCT03439839) evaluating Fabhalta in PNH. They were first tested while on Soliris, then after switching to Fabhalta — initially in combination with Soliris and later as Fabhalta alone.
Rather than measuring only residual complement activity, the researchers examined small protein fragments produced when different parts of the complement system are activated. These included Bb, which reflects early complement activation; sC5b-9, a marker of activity at the final stage of the cascade; and C4d, which signals activation via the classical complement pathway, an upstream pathway not directly targeted by these drugs.
The team then compared these biomarker levels with standard measures of disease activity, especially LDH, a well-established marker of hemolysis.
In untreated patients, blood levels of Bb and sC5b-9 were markedly elevated, confirming intense, ongoing activation of the complement system. C4d levels, however, remained within the normal range, supporting the idea that hemolysis in PNH is not primarily driven by that pathway.
Across all treatment settings — those receiving Fabhalta or Voydeya, or combination therapy with Soliris plus Fabhalta — complement biomarker levels changed in ways that were consistent with the drugs’ mechanisms of action.
Biomarker patterns reflect drug mechanisms but not disease activity
For example, patients receiving Soliris showed persistently high Bb levels — indicating that early complement activation was still occurring — while sC5b-9 levels were lower than in untreated patients, reflecting reduced activation of the final stage of the cascade. Among patients receiving either Fabhalta or Voydeya alone, or combination therapy, both Bb and sC5b-9 levels were lower than in untreated disease, though still above normal levels.
However, levels of Bb and sC5b-9 did not consistently match clinical signs of hemolysis. They often fluctuated in a way that did not reflect changes in hemolysis, as assessed with LDH, or remained elevated even when LDH showed good control of hemolysis.
Overall, the findings suggest that while complement fragments like Bb and sC5b-9 “may be informative to track” residual complement activity or “possible leakages” in complement inhibition, they are not reliable on their own for monitoring disease activity or predicting hemolysis in people with PNH, the researchers noted.
“In this setting, LDH seems more informative to track hemolysis associated with residual complement activation,” the team concluded.
